Arylsulfonamides as antiviral agents

ABSTRACT

The present invention relates to novel sulphonamides of the general formula (I)  
                 
 
     in which the substituents R 1 , R 2 , R 3 , R 4  and A and X are as defined above, and also to processes for their preparation and to their use as antiviral agents, in particular against cytomegaloviruses.

[0001] The present invention relates to novel compounds, to processesfor their preparation and to their use as medicaments, in particular asantiviral agents, in particular against cytomegaloviruses.

[0002] From WO 99/37291, compound2,2-dimethyl-N-[4-[[[4-(4-phenyl-2H-1,2,3-triazol-2-yl)phenyl]-sulphonyl]amino]phenyl]-propanamideis known as having antiviral action.

[0003] The present invention relates to compounds of the general formula(I)

[0004] in which

[0005] R² and R³ are identical or different and represent hydrogen,hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or represent a group of the formula

[0006] in which

[0007] R⁵, R⁶ and R⁷ are identical or different and each representshydrogen or (C₁-C₆)-alkyl which for its part may be substituted by oneor two substituents selected from the group consisting of hydroxyl,halogen, cyano, trifluoromethyl and trifluoromethoxy,

[0008] A represents five- or six-membered heteroaryl, which is attachedto the adjacent phenyl ring via a C atom and has one to threeheteroatoms selected from the group consisting of N, O and S,

[0009] R¹ represents (C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl or 5-to 10-membered heterocyclyl having in each case one to three heteroatomsselected from the group consisting of N, O and S, where

[0010] R¹ may be substituted by up to three substituents selected fromthe group consisting of hydroxyl, amino, mono-(C₁-C₆)-alkylamino,di-(C₁-C₆)-alkylamino, halogen, nitro, cyano, oxo, (C₁-C₆)-alkyl, whichfor its part may be substituted by amino or hydroxyl, (C₁-C₆)-alkoxy,phenyl, 5- or 6-membered heterocyclyl having up to two heteroatomsselected from the group consisting of N, O and S, 5- or 6-memberedheteroaryl having one or more heteroatoms selected from the groupconsisting of N, O and S, —C(O)—O—R⁸, —C(O)—NR⁹R¹⁰, —NH—C(O)—R¹¹,—NH—C(O)—C(O)—R¹² and —NH—SO₂—R¹³, where

[0011] R⁸, R⁹ and R¹⁰ are identical or different and each representshydrogen or (C₁-C₆)-alkyl, or

[0012] R⁹ and R¹⁰ together with the nitrogen atom to which they areattached form a 5- or 6-membered heterocycle which may contain a furthernitrogen-or oxygen heteroatom and which may be mono- or disubstituted byidentical or different substituents from the group consisting of(C₁-C₄)-alkyl, which for its part is optionally substituted by hydroxylor amino, amino, hydroxyl, (C₁-C₄)-alkoxy, oxo, carboxyl and(C₁-C₄)-alkoxycarbonyl,

[0013] R¹¹ and R¹² are identical or different and each representstrifluoromethyl, (C₁-C₆)-alkoxy, hydroxyl, or represents (C₁-C₆)-alkyl,which is optionally mono- or disubstituted by identical or differentconstituents from the group consisting of amino,(C₁-C₆)-alkoxycarbonylamino, mono-(C₁-C₆)-acylamino, hydroxyl, amidino,guanidino, (C₁-C₆)-alkoxycarbonyl, carboxyl and phenyl, and

[0014] R¹³ represents (C₁-C₆)-alkyl or (C₆-C₁₀)-aryl which may in eachcase be substituted by halogen, amino, hydroxyl, (C₁-C₄)-alkoxy or(C₁-C₄)-alkyl,

[0015] R⁴ represents (C₁-C₆)-alkyl which may be substituted up to threetimes by identical or different substituents from the group consistingof amino, hydroxyl, halogen, (C₁-C₆)-alkoxy, (C₁-C₅)-alkanoyloxy andphenyl, which for its part is optionally mono- or disubstituted byidentical or different substituents from the group consisting ofhalogen, nitro, cyano, amino and hydroxyl,

[0016] represents (C₃-C₇)-Cycloalkyl which may be substituted up tothree times by identical or different substituents from the groupconsisting of amino, hydroxyl, halogen, (C₁-C₆)-alkoxy and(C₁-C₆)-alkyl, which for its part is optionally substituted up to threetimes by identical or different substituents from the group consistingof amino, hydroxyl, halogen and (C₁-C₆)-alkoxy, or represents(C₆-C₁₀)-aryl which is optionally mono- or disubstituted by identical ordifferent substituents from the group consisting of halogen, nitro,cyano, amino and hydroxyl,

[0017] and in which

[0018] X represents oxygen or sulphur,

[0019] and in which nitrogen-containing heterocycles may also be presentas N-oxides,

[0020] and their tautomers, stereoisomers, stereoisomer mixtures andtheir pharmacological acceptable salts.

[0021] In the context of the invention, (C₁-C₆)-alkyl represents astraight-chain or branched alkyl radical having 1 to 6 carbon atoms. Thefollowing radicals may be mentioned by way of example: methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl and n-hexyl.

[0022] In the context of the invention, (C₃-C₇)-cycloalkyl represents acycloalkyl group having 3 to 7 carbon atoms. The following radicals maybe mentioned by way of example: cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

[0023] In the context of the invention, (C₁-C₆)-alkoxy represents astraight-chain or branched alkoxy radical having 1 to 6 carbon atoms.The following radicals may be mentioned by way of example: methoxy,ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.Preference is given to methoxy and ethoxy.

[0024] In the context of the invention, (C₆-C₁₀)-aryl represents anaromatic radical having 6 to 10 carbon atoms. Preferred aryl radicalsare phenyl and naphthyl.

[0025] In the context of the invention, aralkyl represents(C₆-C₁₀)-aryl, which for its part is attached to (C₁-C₄)-alkyl.Preference is given to benzyl.

[0026] In the context of the invention, mono-(C₁-C₆)-alkylaminorepresents an amino group having a straight-chain, branched or cyclicalkyl substituent having 1 to 6 carbon atoms. The following radicals maybe mentioned by way of example: methylamino, ethylamino, n-propylamino,isopropylamino, cyclopropylamino, t-butylamino, n-pentylamino,cyclopentylamino and n-hexylamino.

[0027] In the context of the invention, di-(C₁-C₆)-alkylamino representsan amino group having two identical or different straight-chain,branched or cyclic alkyl substituents, having in each case 1 to 6 carbonatoms. The following radicals may be mentioned by way of example:N,N-dimethylamino, N,N-diethyl amino, N-ethyl-N-methylamino,N-methyl-N-n-propylamino, N-methyl-N-cyclopropylamino,N-isopropyl-N-n-propyl-amino, N-t-butyl-N-methylamino,N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.

[0028] In the context of the invention, (C₁-C₆)-alkoxycarbonylrepresents a straight-chain or branched alkoxy-radical having 1 to 6carbon atoms, which is attached via a carbonyl group. Preference isgiven to a straight-chain or branched alkoxycarbonyl radical having 1 to4 carbon atoms. The following radicals may be mentioned by way ofexample and by way of preference: methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.

[0029] In the context of the invention, (C₁-C₆)-alkoxycarbonylaminorepresents an amino group having a straight-chain or branchedalkoxycarbonyl substituent which has 1 to 6 carbon atoms in the alkoxyradical and is attached via the carbonyl group. Preference is given toan alkoxycarbonylamino radical having 1 to 4 carbon atoms in the alkoxyradical. The following radicals may be mentioned by way of example andby way of preference: methoxycarbonylamino, ethoxycarbonylamino,n-propoxy-carbonylamino and t-butoxycarbonylamino.

[0030] In the context of the invention, mono-(C₁-C₆)-acylaminorepresents an amino group having a straight-chain or branched alkanoylsubstituent which has 1 to 6 carbon atoms and is attached via thecarbonyl group. Preference is given to a monoacylamino radical having 1or 2 carbon atoms. The following radicals may be mentioned by way ofexample and by way of preference: formamido, acetamido, propionamido,n-butyramido and pivaloylamido.

[0031] In the context of the invention, (C₁-C₅)-alkanoyloxy preferablyrepresents a straight-chain or branched alkyl radical having 1 to 5carbon atoms which carries a doubly attached oxygen atom in the1-position and which is attached in the 1-position via a further oxygenatom. Preference is given to a straight-chain or branched alkanoyloxyradical having 1 to 3 carbon atoms. The following radicals may bementioned by way of example and by way of preference: acetoxy,propionoxy, n-butyroxy, i-butyroxy and pivaloyloxy.

[0032] In the context of the invention, halogen generally representsfluorine, chlorine, bromine and iodine. Preference is given to fluorine,chlorine and bromine. Particular preference is given to fluorine andchlorine.

[0033] In the context of the invention, 5- to 10-membered heteroarylrepresents 5- to 10-membered hetero-containing aromatic rings which maycontain 1 to 4 heteroatoms selected from the group consisting of O, Sand N, including, for example: pyridyl, furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolicenyl,indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl,isoquinolyl, naphthyridinyl, quinazolinyl, etc.

[0034] In the context of the invention, 5- to 10-membered or 5- or6-membered saturated or partially unsaturated heterocyclyl having up to3 heteroatoms from the croup consisting of S. N and O generallyrepresents a mono- or bicyclic heterocycle which may contain one or moredouble bonds and which is attached via a ring carbon atom or a ringnitrogen atom. The following radicals may be mentioned by way ofexample: tetrahydrofur-2-yl, tetrahydrofur-3-yl, pyrrolidin-1-yl,pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolin-1-yl, piperidin-1-yl,piperidin-3-yl, 1,2-dihydropyridin-1-yl, 1,4-dihydropyridin-1-yl,piperazin-1-yl, morpholin-1-yl, azepin-1-yl, 1,4-diazepin-1-yl.Preference is given to piperidinyl, morpholinyl and pyrrolidinyl.

[0035] 1,2,4-Oxadiazole which is attached via the 3- or 5-positionrepresents an oxadiazole which is attached to the phenylsulphonamide viathe ring carbon atom in the 3- or 5-position.

[0036] In the context of the invention, the preferred salts arepharmacologically acceptable salts of the compounds according to theinvention.

[0037] Pharmacologically acceptable salts of the compounds according tothe invention may be acid addition salts of the compounds according tothe invention with mineral acids, carboxylic acids or sulphonic acids.Particular preference is given, for example, to salts with hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid,maleic acid or benzoic acid.

[0038] However, salts that may be mentioned include salts with customarybases, such as, for example, alkali metal salts (for example sodiumsalts or potassium salts), alkaline earth metal salts (for examplecalcium salts or magnesium salts) or ammonium salts, derived fromammonia or organic amines, such as, for example, diethylamine,triethylamine, ethyldiusopropylamine, procaine, dibenzylamine,N-methylmorpholine, dihydroabietylamine, 1-ephenamine ormethylpiperidine, or derived from natural amino acids, such as, forexample, glycine, lysine, arginine or histidine.

[0039] The compounds according to the invention may exist instereoisomeric forms which are either like image and mirror image(enantiomers) or which are not like image and mirror image(diastereomers). The invention relates both to the enantiomers ordiastereomers and to their respective mixtures. The racemic forms can,like the diastereomers, be separated into the stereoisomerically uniformcomponents in a manner known per se.

[0040] In addition, the invention also embraces prodrugs of thecompounds according to the invention. According to the invention,prodrugs are derivatives of the compounds of the general formula (I)which for their part may be biologically less active or even inactive,but, following administration, are converted under physiologicalconditions into the corresponding biologically active form (for examplemetabolically, solvolytically or in another manner).

[0041] The invention also relates to compounds of the general formula(1),

[0042] in which

[0043] R² and R³ are identical or different and represent hydrogen,hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or represent a group of the formula

[0044] in which

[0045] R⁵, R⁶ and R⁷ are identical or different and each representshydrogen or (C₁-C₆)-alkyl, which for its part may be substituted by oneor two substituents selected from the group consisting of hydroxyl,halogen, cyano, trifluoromethyl and trifluoromethoxy,

[0046] A represents five- or six-membered heteroaryl, which is attachedto the adjacent phenyl ring via a C atom and has one to threeheteroatoms selected from the group consisting of N, O and S,

[0047] R¹ represents (C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl or 5-to 10-membered heterocyclyl having in each case one to three heteroatomsselected from the group consisting of N, O and S, where

[0048] R¹ may be substituted by up to three substituents selected fromthe group consisting of hydroxyl, amino, mono-(C₁-C₆)-alkylamino,di-(C₁-C₆)-alkylamino, halogen, nitro, cyano, oxo, (C₁-C₆)-alkyl, whichfor its part may be substituted by amino or hydroxyl, (C₁-C₆)-alkoxy,phenyl, 5- or 6-membered heteroaryl having one or more heteroatomsselected from the group consisting of N, O and S, —C(O)—O—R⁸,—C(O)—NR⁹R¹⁰ and —NH—C(O)—R¹¹,

[0049] where

[0050] R⁸, R⁹ and R¹⁰ are identical or different and each representshydrogen or (C₁-C₆)-alkyl,

[0051] and

[0052] R¹¹ represents (C₁-C₆)-alkyl which is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of amino, hydroxyl, guanidino, carboxyl and phenyl,

[0053] R⁴ represents (C₁-C₆)-alkyl which may be substituted up to threetimes by identical or different substituents from the group consistingof amino, hydroxyl, halogen, (C₁-C₆)-alkoxy and phenyl, which for itspart is optionally mono- or disubstituted by identical or differentsubstituents from the group consisting of halogen, nitro, cyano, aminoand hydroxyl,

[0054] represents (C₃-C₇)-cycloalkyl which may be substituted up tothree times by identical or different substituents from the groupconsisting of amino, hydroxyl, halogen, (C₁-C₆)-alkoxy and(C₁-C₆)-alkyl, which for its part is optionally substituted up to threetimes by identical or different substituents from the group consistingof amino, hydroxyl, halogen and (C₁-C₆)-alkoxy,

[0055] or represents (C₆-C₁₀)-aryl which is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of halogen, nitro, cyano, amino and hydroxyl,

[0056] and in which

[0057] X represents oxygen or sulphur,

[0058] and in which nitrogen-containing heterocycles may also be presentas N-oxides,

[0059] and their tautomers, stereoisomers, stereoisomer mixtures andtheir pharmacologically acceptable salts.

[0060] The invention preferably relates to compounds of the generalformula (I),

[0061] in which

[0062] R² and R³ are identical or different and represent hydrogen,hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or represent a group of the formula

[0063] in which

[0064] R⁵, R⁶ and R⁷ are identical or different and each representshydrogen or (C₁-C₆)-alkyl, which for its part may be substituted by oneor two substituents selected from the group consisting of hydroxyl,halogen, cyano, trifluoromethyl and trifluoromethoxy,

[0065] A represents five- or six-membered heteroaryl, which is attachedto the adjacent phenyl ring via a C atom and has one to threeheteroatoms selected from the group consisting of N, O and S,

[0066] R¹ represents (C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl or 5-to 10-membered heterocyclyl having in each case one to three heteroatomsselected from the group consisting of N, O and S, where

[0067] R¹ may be substituted by up to three substituents selected fromthe group consisting of hydroxyl, amino, mono-(C₁-C₆)-alkylamino,di-(C₁-C₆)-alkylamino, halogen, nitro, cyano, oxo, (C₁-C₆)-alkyl, whichfor its part may be substituted by amino or hydroxyl, (C₁-C₆)-alkoxy,phenyl, 5- or 6-membered heteroaryl having one or more heteroatomsselected from the group consisting of N, O and S, —C(O)—O—R⁸,—C(O)—NR⁹R¹⁰ and —NH—C(O)—R¹¹,

[0068] where

[0069] R⁸, R⁹ and R¹⁰ are identical or different and each representshydrogen or (C₁-C₆)-alkyl,

[0070] and

[0071] R¹¹ represents (C₁-C₆)-alkyl, which is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of amino, hydroxyl, guanidino, carboxyl and phenyl,

[0072] R⁴ represents (C₁-C₆)-alkyl which may be substituted up to threetimes by identical or different substituents from the group consistingof amino, hydroxyl, halogen, (C₁-C₆)-alkoxy and phenyl, which for itspart is optionally mono- or disubstituted by identical or differentsubstituents from the group consisting of halogen, nitro, cyano, aminoand hydroxyl,

[0073] represents (C₃-C₇)-cycloalkyl which may be substituted up tothree times by identical or different substituents from the groupconsisting of amino, hydroxyl, halogen, (C₁-C₆)-alkoxy and(C₁-C₆)-alkyl, which for its part is optionally substituted up to threetimes by identical or different substituents from the group consistingof amino, hydroxyl, halogen and (C₁-C₆)-alkoxy,

[0074] or represents (C₆-C₁₀)-aryl which is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of halogen, nitro, cyano, amino and hydroxyl,

[0075] and in which

[0076] X represents oxygen,

[0077] and in which nitrogen-containing heterocycles may also be presentas N-oxides,

[0078] and their tautomers, stereoisomers, stereoisomer mixtures andtheir pharmacologically acceptable salts.

[0079] The invention preferably also relates to compounds of the generalformula (I),

[0080] in which

[0081] R² and R³ are identical or different and represent hydrogen orhalogen,

[0082] A represents the radical (A-I)

[0083] which is attached to the adjacent phenyl ring via one of thecarbon atoms in position 3 or 5,

[0084] and in which

[0085] Y represents oxygen or sulphur,

[0086] or

[0087] A represents the radical (A-II)

[0088] which is attached to the adjacent phenyl ring via one of thecarbon atoms in position 2 or 5,

[0089] and in which

[0090] Y represents oxygen or sulphur,

[0091] R¹ represents 5- to 10-membered heteroaryl or 5- or 10-memberedheterocyclyl having in each case up to three heteroatoms selected fromthe group consisting of N, O and S, or represents phenyl, where

[0092] R¹ may be substituted by one to three substituents selected fromthe group consisting of (C₁-C₄)-alkyl, which for its part is optionallysubstituted by hydroxyl or amino, hydroxyl, oxo, halogen, amino,mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino and —NH—C(O)—R¹¹,

[0093] where

[0094] R¹¹ represents (C₁-C₆)-alkyl which is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of amino, hydroxyl, guanidino and carboxyl,

[0095] R⁴ represents (C₁-C₄)-alkyl which may be substituted up to threetimes by identical or different substituents from the group consistingof amino, hydroxyl, fluorine, chlorine and (C₁-C₄)-alkoxy,

[0096] represents (C₃-C₅)-cycloalkyl, which may be substituted up tothree times by identical or different substituents from the groupconsisting of amino, hydroxyl, fluorine, chlorine, (C₁-C₄)-alkoxy and(C₁-C₄)-alkyl, which for its part is optionally substituted up to threetimes by identical or different substituents from the group consistingof amino, hydroxyl, fluorine, chlorine and (C₁-C₄)-alkoxy,

[0097] and in which

[0098] X represents oxygen or sulphur,

[0099] and in which nitrogen-containing heterocycles may also be presentas N-oxides,

[0100] and their tautomers, stereoisomers, stereoisomer mixtures andtheir pharmacologically acceptable salts.

[0101] The invention particularly preferably relates to compounds of thegeneral formula (I),

[0102] in which

[0103] R² and R³ are identical or different and represent hydrogen orhalogen,

[0104] A represents the radical (A-I)

[0105] which is attached to the adjacent phenyl ring via one of thecarbon atoms in position 3 or 5,

[0106] and in which

[0107] Y represents oxygen or sulphur,

[0108] or

[0109] A represents the radical (A-II)

[0110] which is attached to the adjacent phenyl ring via one of thecarbon atoms in position 2 or 5,

[0111] and in which

[0112] Y represents oxygen or sulphur,

[0113] R¹ represents 5- to 10-membered heteroaryl or 5- or 10-memberedheterocyclyl having in each case up to three heteroatoms selected fromthe group consisting of N, O and S, or represents phenyl, where

[0114] R¹ may be substituted by one to three substituents selected fromthe group consisting of (C₁-C₄)-alkyl, which for its part is optionallysubstituted by hydroxyl or amino, hydroxyl, oxo, halogen, amino,mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino and —NH—C(O)—R¹¹,

[0115] where

[0116] R¹¹ represents (C₁-C₆)-alkyl which is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of amino, hydroxyl, guanidino and carboxyl,

[0117] R⁴ represents (C₁-C₄)-alkyl which may be substituted up to threetimes by identical or different substituents from the group consistingof amino, hydroxyl, fluorine, chlorine and (C₁-C₄)-alkoxy, or

[0118] represents (C₃-C₅)-cycloalkyl which may be substituted up tothree times by identical or different substituents from the groupconsisting of amino, hydroxyl, fluorine, chlorine, (C₁-C₄)-alkoxy and(C₁-C₄)-alkyl, which for its part is optionally substituted up to threetimes by identical or different substituents from the group consistingof amino, hydroxyl, fluorine, chlorine and (C₁-C₄)-alkoxy,

[0119] and in which

[0120] X represents oxygen,

[0121] and their tautomers, stereoisomers, stereoisomer mixtures andtheir pharmacologically acceptable salts.

[0122] The invention particularly preferably relates to compounds of thegeneral formula (I),

[0123] in which

[0124] R² and R³ represent hydrogen,

[0125] A represents one of the radicals

[0126] R¹ represents a radical selected from the group consisting ofphenyl, pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl,isoquinolinyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and indolyl,where

[0127] R¹ may be substituted by one or two substituents selected fromthe group consisting of methyl, aminomethyl, hydroxyl, bromine,chlorine, fluorine, amino, dimethylamino and —NH—C(O)—R¹¹,

[0128] where

[0129] R¹¹ represents (C₁-C₆)-alkyl which is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of amino, hydroxyl, guanidino and carboxyl,

[0130] R⁴ represents tert-butyl which is optionally substituted up tothree times by identical or different substituents from the groupconsisting of hydroxyl, fluorine and chlorine, or

[0131] represents cyclopropyl or cyclobutyl which are substituted bymethyl, which for its part is optionally substituted by hydroxyl,fluorine or chlorine,

[0132] and in which

[0133] X represents oxygen,

[0134] and in which nitrogen-containing heterocycles may also be presentas N-oxides,

[0135] and their tautomers, stereoisomers, stereoisomer mixtures andtheir pharmacologically acceptable salts.

[0136] With particular preference, the invention relates to compounds ofthe general formula (1),

[0137] in which

[0138] R² and R³ represent hydrogen,

[0139] A represents one of the radicals

[0140] R¹ represents a radical selected from the group consisting (ofphenyl, pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl,isoquinolinyl, oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and indolyl,where

[0141] R¹ may be substituted by one or two substituents selected fromthe group consisting of methyl, aminomethyl, hydroxyl, bromine,chlorine, fluorine, amino, dimethylamino and —NH—C(O)—R¹¹,

[0142] where

[0143] R¹¹ represents (C₁-C₆)-alkyl which is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of amino, hydroxyl, guanidino and carboxyl,

[0144] R⁴ represents tert-butyl which is optionally substituted up tothree times by identical or different substituents from the groupconsisting of hydroxyl fluorine and chlorine, or

[0145] represents cyclopropyl or cyclobutyl which are substituted bymethyl, which for its part is optionally substituted by hydroxyl,fluorine- or chlorine,

[0146] and in which

[0147] X represents oxygen.

[0148] In a preferred embodiment, the invention relates to compounds ofthe general formula (Ia)

[0149] in which

[0150] R¹, R⁴, A and X are as defined above,

[0151] and

[0152] R² and R³ are identical or different and represent hydrogen,hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,(C₁-C₆)-alkyl or (C₁-C₆)-alkoxy.

[0153] In a further preferred embodiment, the invention relates tocompounds of the general formula (1),

[0154] in which

[0155] R⁴ represents one of the radicals

[0156] In a further preferred embodiment, the invention relates tocompounds of the general formula (I),

[0157] in which

[0158] A represents 1,2,4-oxadiazole which is attached via the3-position.

[0159] Very particularly preferred compounds of the present inventionare sulphonamides which are selected from the group of the followingcompounds:

[0160] The invention furthermore relates to processes for preparingcompounds of the general formula (I), which are characterized in that

[0161] [A] nitro-anilines of the general formula [A-1]

[0162] in which

[0163] R³ has the meaning given above,

[0164] are reacted with compounds of the general formula [A-2]

[0165] in which

[0166] X and R⁴ have one of the meanings given above,

[0167] and

[0168] Q represents a leaving group, for example halogen, preferablychlorine or bromine,

[0169] in inert solvents in the presence of a base to give compounds ofthe general formula [A-3]

[0170] in which

[0171] X, R³ and R⁴ have one of the meanings given above,

[0172] and

[0173] [B] the nitro-aromatic compounds of the general formula [A-3] arereduced in inert solvents, for example in the presence of transitionmetal catalysts and hydrogen, to aromatic amines of the general formula[B-1]

[0174] in which

[0175] X, R³ and R⁴ have one of the meanings given above,

[0176] and

[0177] [C] amines of the general formula [B-1] are reacted withsulphonic acid derivatives of the general formula [C-1]

[0178] in which

[0179] R² has the meaning given above,

[0180] and

[0181] Z represents a leaving group, for example halogen, preferablychlorine or bromine,

[0182] in inert solvents, in the presence of a base, to give compoundsof the general formula [C-2]

[0183] in which

[0184] X, R², R³ and R⁴ have one of the meanings given above,

[0185] and

[0186] [D] the nitriles of the general formula [C-2] are reacted inpolar protic solvents, for example alcohols, at elevated temperature,preferably the boiling point of the solvent, in the presence of a basewith hydroxylarine to give amidoximes of the general formula [D-1]

[0187] in which

[0188] X, R², R³ and R⁴ have one of the meanings given above,

[0189] and

[0190] [E] amidoximes of the general formula [D-1] are acylated with acarboxylic acid of the general formula [E-1]

R¹—COOH  [E-1]

[0191] in which

[0192] R¹ has the meaning given above,

[0193] in the presence of a condensing agent, for examplebenzotriazolyl-N-oxi-tris(dimethylamino)phosphonium hexafluorophosphate(PyBOP), or other activating agents known from peptide chemistry, andalso acid chlorides, and a base in a polar aprotic solvent, for exampletetrahydrofuran, and the acylated amidoxime is isolated as a crudeproduct and then cyclized in a high-boiling polar solvent, for exampleDMF, at elevated temperature, to give the 1,2,4-oxadiazole.

[0194] The process according to the invention for preparing1,2,4-oxadiazoles attached via the 3-position is illustrated in anexemplary manner by the formula scheme below:

[0195] The invention furthermore relates to processes for preparingcompounds of the general formula (I), characterized in that

[0196] [F] sulphonyl halides of the general formula [F-1]

[0197] in which

[0198] R² and Z have the meaning given above,

[0199] and

[0200] R^(F-1) represents (C₁-C₄)-alkyl, aralkyl or a carboxylic acidprotective group,

[0201] are reacted in the presence of a base with anilines of thegeneral formula [B-1] to give sulphonamides of the general formula [F-2]

[0202] in which

[0203] R^(F-1), R², R³, R⁴ and X have the meaning given above,

[0204] and the group R^(F-1) is then cleaved off from the compounds ofthe general formula [F-2], for example in the presence of hydroxylanions, giving sulphonamides of the general formula [F-3],

[0205] and

[0206] [G] amid-oximes of the general formula [G-1]

[0207] in which

[0208] R¹ has the meaning given above,

[0209] are condensed with compounds of the general formula [F-3] to givecompounds of the general formula [G-2],

[0210] in which

[0211] R¹, R², R³, R⁴ and X have the meaning given above, and

[0212] [H] compounds of the general formula [G-2] are cyclized thermallyto give the 1,2,4-oxadiazoles, attached via the 5-position, of thegeneral formula [H-1]

[0213] in which

[0214] R¹, R², R³, R⁴ and X have the meaning given above.

[0215] The compounds according to the invention can be prepared, forexample, according to the formula scheme below:

[0216] Solvents suitable for all process steps are the customary inertsolvents which do not change under the reaction conditions. Thesepreferably include organic solvents, such as ethers, for example diethylether, glycol monomethyl ether or glycol dimethyl ether, dioxane ortetrahydrofuran, or alcohols, such as methanol, ethanol, n-propanol,iso-propanol, n-butanol or tert-butanol, or hydrocarbons, such asbenzene, toluene, xylene, cyclohexane or mineral oil fractions, orhalogenated hydrocarbons, such as methylene chloride, chloroform orcarbon tetrachloride, or dimethyl sulphoxide, dimethylformamide,hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine orpicoline. It is also possible to use mixtures of the solvents mentioned,if appropriate also with water. Particular preference is given tomethylene chloride, tetrahydrofuran, dioxane and dioxane/water and inparticular to the solvents mentioned in the section “GeneralProcedures”.

[0217] Suitable bases are organic amines, such astri-(C₁-C₆)-alkylamines, for example triethylamine, or heterocycles,such as pyridine, methylpiperidine, piperidine or N-methylmorpholine.Preference is given to triethylamine and pyridine.

[0218] The bases are generally employed in an amount of from 0.1 mol to5 mol, preferably from 1 mol to 3 mol, in each case based on 1 mol ofthe compounds of the general formulae [A-1], [B-1], [C-2], [D-1] and[E-1].

[0219] The reactions can be carried out at atmospheric pressure, butalso at elevated or reduced pressure (for example from 0.5 to 3 bar). Ingeneral, the reactions are carried out at atmospheric pressure.

[0220] The reactions are carried out in a temperature range of from 0°C. to 150° C., preferably from 0° C. to 30° C., and at atmosphericpressure. The conversion of the compounds [G-2] into [H-1] is carriedout at elevated temperature, preferably at temperatures above 100° C.

[0221] The reductions can generally be-carried out using hydrogen ininert organic solvents, such as dimethylformamide, alcohols, ethers oracetic esters, or mixtures thereof, using catalysts such asRaney-nickel, palladium, palladium on carbon or platinum, or usinghydrides or boranes, or using inorganic reducing agents, such as, forexample, tin(II) chloride, in inert solvents, if appropriate in thepresence of a catalyst. Preference is given to palladium on carbon.

[0222] The reaction can be carried out at atmospheric or at elevatedpressure (for example from 1 to 5 bar). In general, the reaction iscarried out at atmospheric pressure. Hydrogenations are preferablycarried out under elevated pressure, in general at 3 bar.

[0223] The reductions are generally carried out in a temperature rangeof from 0° C. to +60° C., preferably at from +10° C. to +40° C.

[0224] Solvents which are suitable for the acylation are customaryorganic solvents which do not change under the reaction conditions.These preferably include ethers, such as diethyl ether, dioxane,tetrahydrofuran or glycol dimethyl ether, or hydrocarbons, such asbenzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions,or halogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, dichloroethylene, trichloroethylene orchlorobenzene, or ethyl acetate, or triethylamine, pyridine,dimethylformamide, acetonitrile or acetone. It is also possible to usemixtures of the solvents mentioned. Preference is given todichloromethane, tetrahydrofuran and pyridine.

[0225] The acylation is carried out in the solvents listed above, attemperatures of from 0° C. to +150° C., preferably at from roomtemperature to +100° C., and at atmospheric pressure.

[0226] The compounds of the general formulae [A-1], [A-2], [C-1], [E-1],[F-1] and [G-1] are known per se or can be prepared by methods knownfrom the literature.

[0227] Further compounds of the general formula (I) in which Arepresents a 1,3,4-oxadiazole can be prepared, for example, on apolymeric support using the IRORI system according to the “Split & Mix”method, as shown below in Scheme 4:

[0228] Compounds of the general formula (I) are furthermore obtained,for example, by a process according to Scheme 5 which is carried out ina mixed procedure involving solid-phase synthesis and synthesis insolution.

[0229] The processes shown in Schemes 4 and 5 also permit thepreparation of further compounds of the general formula (I) according tothe invention in which

[0230] X represents oxygen

[0231] and

[0232] A represents the radical (A-II)

[0233] which is attached to the adjacent phenyl ring via one of thecarbon atoms in position 2 or 5,

[0234] and in which

[0235] Y represents oxygen,

[0236] by cyclizing hydrazides of the general formula [H-2]

[0237] in which X, R¹, R², R³, R⁴ have one of the meanings given above,

[0238] and

[0239] FH represents hydrogen, an amino protective group or a polymericsupport,

[0240] with elimination of water, to give the compounds of the generalformula (I).

[0241] They further permit the preparation of compounds of the generalformula (I) in which

[0242] X represents oxygen

[0243] and

[0244] A represents the radical (A-II)

[0245] which is attached to the adjacent phenyl ring via one of thecarbon atoms of position 2 or 5,

[0246] and in which

[0247] Y represents sulphur,

[0248] by cyclizing hydrazides of the general formula [H-3]

[0249] in which R¹, R², R³ are as defined above,

[0250] FH represents hydrogen, an amino protective group or a polymericsupport,

[0251] and

[0252] R^(4′) represents (C₁-C₆)-alkoxy, (C₁-C₆)-alkenoxy or aralkoxy,

[0253] in the presence of a thio donor, preferably Lawesson's reagent,to give compounds of the general formula (I) in which Y representssulphur, then removing group —C(O)—R^(4′) and finally reacting withcompounds of the general formula

[0254] in which R⁴ and Q are as defined above.

[0255] The compounds of the general formula (I) according to theinvention show a surprising range of actions which could not have beenpredicted. They show an antiviral action on representatives of the groupof the Herpes viridae, in particular on human cytomegalovirus (HCMV).They are thus suitable for the treatment and prophylaxis of disorderscaused by Herpes viridae, in particular disorders caused by humancytomegaloviruses.

[0256] Owing to their particular properties, the compounds of thegeneral formula (1) can be used for preparing medicaments suitable forthe prophylaxis or treatment of diseases, in particular viral disorders.

[0257] Owing to their properties, the compounds according to theinvention are useful active compounds for the treatment and prophylaxisof infections by human cytomegaloviruses and disorders caused by theseinfections. Examples of areas of indication which may be mentioned are:

[0258] 1) Treatment and prophylaxis of HCMV infections in AIDS patients(retinitis, pneumonitis, gastrointestinal infections).

[0259] 2) Treatment and prophylaxis of cytomegalovirus infections inbone marrow and organ transplant patients who often sufferlife-threatening HCMV pneumonitis or encephalitis, or gastrointestinalor systemic HCMV infections.

[0260] 3) Treatment and prophylaxis of HCMV infections in neonates andin infants.

[0261] 4) Treatment of an acute HCMV infection in pregnant women.

[0262] 5) Treatment of HCMV infections in immunosuppressed patientssuffering from cancer and undergoing cancer therapy.

[0263] The novel active compounds can be used on their own and, ifrequired, also in combination with other antiviral active compounds,such as, for example, gancycloyir or acylovir.

[0264] Descriptions of Biological Tests:

[0265] In Vitro Action:

[0266] Anti-HCMV (Anti-Human Cytomegalovirus) and anti-MCMV (Anti-MurineCytomegalovirus) cytopathogenicity tests:

[0267] The test compounds were employed as 50 millimolar (mM) solutionsin dimethyl sulphoxide (DMSO). Ganciclovir, foscarnet and cidofovirserved as reference compounds. Following the addition of in each case 2μl of the 50, 5, 0.5 and 0.05 mM DMSO stock solutions to in each case98μ of cell culture medium in row 2 A-H, in duplicate determinations,1:2 dilutions with in each case 50 μl of medium were prepared up to row11 of the 96-well plate. The wells in rows 1 and 12 each contained 50 μlof medium. 150 μl of a suspension of 1×10⁴ cells (human lung fibroblasts[HELF]) (row 1=cell control) or, in rows 2-12, a mixture ofHCMV-infected and non-infected HELF cells (M.O.I.=0.001-0.002), i.e. 1-2infected cells per 1000 non-infected cells, were then pipetted into eachof the wells. Row 12 (without substance) served as virus control. Thefinal test concentrations were 250-0.0005 μM. The plates were incubatedat 37° C./5% CO₂ for 6 days, i.e. until all cells in the virus controlshad been infected (100% cytopathogenic effect [CPE]). The wells werethen fixed and stained by adding a mixture of Formalin and Giemsa Stain(30 minutes), washed with doubly distilled water and dried in a dryingcabinet at 50° C. The plates were then evaluated visually using anoverhead microscope (plaque multiplier from Technomara).

[0268] From the test plates, the following data were determined:

[0269] CC₅₀ (HELF)=substance concentration in μM at which, compared tothe untreated cell control, no visible cytostatic effects on the cellswere noticeable;

[0270] EC₅₀ (HCMV)=substance concentration in μM which inhibits the CPE(cytopathic effect) by 50% compared to the untreated virus control;

[0271] SI (selectivity index)=CC₅₀ (HELF)/EC50 (HCMV).

[0272] Compared to the process described above for HCMV, the anti-MCMVtest was carried out with the following changes: a cell-free virussuspension was mixed with a concentrated cell suspension (3T3 mousecells) and incubated for 15 minutes for adsorption of the viruses, andthe suspension was then diluted with medium to 1.3×10⁵ cells/ml with afinal multiplicity of infection (M.O.I.) of from 0.05-0.1, and in eachcase 150 μl were dispensed into the wells. The incubation time was 5days.

[0273] Representative activity data for the compounds according to theinvention are given in Table 1: TABLE 1 HELF 3T3 MCMV Example CC₅₀ HCMVEC₅₀ SI CC₅₀ EC₅₀ SI No. [μM] [μM] HCMV [μM] [μM] MCMV 1 110 0.055 200033 0.019 1737 2 <16 0.05 <320 0.9 0.045 20 3 <140 0.018 <7778 23 0.0082875 4 >63 0.01 >6300 11 0.015 733 5 >16 0.016 >1000 >31 0.014 >2214 639 0.02 2053 2.9 0.041 71 7 47 0.025 1880 12 0.025 480 8 >2.20.02 >110 >3.9 0.024 >163 9 39 0.018 2167 4 0.068 59 10 >3.90.008 >488 >7.8 0.007 >975 11 >16 0.015 >1040 >12 0.002 >5850 12 140.058 241 7 0.058 121 13 <8 0.04 <200 <16 0.03 <533 131 >28 0.02 >1555132 47 0.006 7833 2.3 0.003 767 134 94 0.009 10444 8 0.0047 1617 135 470.0052 9039 3 0.011 273

[0274] In Vivo Action:

[0275] MCMV Lethality Test:

[0276] Animals:

[0277] 2-3-week old female immunocompetent mice (12-14 g), strain Balb/CAnN or CD1, were purchased from commercial breeders (Bomholtgaard, Iffa,Credo). The animals were not kept under sterile conditions.

[0278] Virus Cultivation:

[0279] Murine cytomegalovirus (MCMV), Smith strain, was passagedrepeatedly in vivo in female CD1 mice. 21 days after intraperitonealinfection (2×10⁴ plaque forming units/0.2 ml/mouse), the salivary glandswere removed, taken up in three times the volume of Minimal EssentialMedium (MEM)+10% foetal calf serum (FCS) and homogenized using anUltraturrax. 10% DMSO v/v were added, 1 ml aliquots were prepared andthe virus suspension was stored at −140° C. Following serial dilution ofthe salivary gland isolate in steps of ten, the titre was determined incell culture for NIH 3T3 cells after staining with Giemsa stain, and thelethal dose was determined in vivo in 2-3 week old Balb/C mice.

[0280] Virus Infection of the Test Animals Treatment and Evaluation:

[0281] 2-3 week old female immunocompetent Balb/C mice (12-14 g) wereinfected intraperitoneally with 3×1 PFU/0.2 ml/mouse. Starting 6 hoursafter the infection, the mice were treated orally with substance twice aday (8.00 and 16.00 hours) for a period of 5 days. The dose was 3, 10,30 or 90 mg/kg of body weight, and the volume administered was 10 ml/kgof body weight. The substances were formulated in the form of a 0.5%strength Tylose suspension, with 2% of DMSO. The placebo-treated controlanimals die within a period of 4-8 days after the infections. Evaluationwas carried out by determining the percentage of surviving animalsfollowing treatment with substance, compared to the placebo-treatedcontrol group.

[0282] HCMV Xenograft Gelfoam® Model:

[0283] Animals:

[0284] 3-4-week old female immunodeficient mice (16-18 g), Fox ChaseSCID or Fox Chase SCID-NOD, were purchased from commercial breeders(Bomholtgaard, Jackson). The animals were kept under sterile conditions(including bedding and feed) in isolators.

[0285] Virus Cultivation:

[0286] Human cytomegalovirus (HCMV) Davis Smith strain, was cultivatedin vitro on human embryonal foreskin fibroblasts (NHDF cells). Thevirus-infected cells were harvested 5-7 days after infection of the NHDFcells with a multiplicity of infection (M.O.I) of 0.01 and stored in thepresence of Minimal Essential Medium (MEM), 10% foetal calf serum (FCS)with 10% DMSO, at −140° C. Following serial dilution of thevirus-infected cells in steps of ten, the titre was determined on24-well plates of confluent NHDF cells, after vital staining withNeutral Red.

[0287] Preparation of the Sponges, Transplantation, Treatment andEvaluation:

[0288] Collagen sponges (dimensions 1×1×1 cm, Gelfoam®; from Peasel &Lorey, order No. 407534; K. T. Chong et al., Abstracts of 39^(th)Interscience Conference on Anti-microbial Agents and Chemotherapy, 1999,p. 439) are initially wetted with phosphate-buffered saline (PBS) andthe enclosed air bubbles are removed by degassing, and the sponges arethen stored in MEM+10% FCS. 3 hours after the infection, 1×10⁶virus-infected NHDF cells (infection with HCMV-Davis M.O.I=0.01) aredetached and, in 20 μl MEM, 10% FCS, added dropwise to a moist sponge.12-13 hours later, the infected sponges are incubated with 5 ng/μl ofbasic Fibroblast Growth Factor (bFGF) in 25 μl of PBS/0.1% BSA/1 mM DTT.For transplantation, the immunodeficient mice are anesthetized withAvertin, the fur on the back is removed using an electric shaver, theepidermis is opened 1-2 cm and relieved and the moist sponges aretransplanted under the skin of the back. The wound caused by the surgeryis closed using tissue glue. 24 hours after the transplantation, themice were treated orally with substance twice daily (8.00 and 16.00hours) over a period of 8 days. The dose was 10 or 30 mg/kg of bodyweight, the administration volume was 10 ml/kg of body weight. Thesubstances were formulated in the form of a 0.5% strength Tylosesuspension with 2% of DMSO. 10 days after the transplantation and 16hours after the last administration of substance, the animals werepainlessly sacrificed and the sponge was removed. The virus-infectedcells were released from the sponge by digestion with coliagenase (330U/1.5 ml) and stored in the presence of MEM, 10% foetal calf serum, 10%DMSO at −140° C. Following serial dilution of the virus-infected cellsin steps of ten, evaluation was carried out by titre determination on24-well plates of confluent NHDF cells, after vital staining withNeutral Red. What was determined was the number of infectious virusparticles after treatment with substance, compared to theplacebo-treated control group.

[0289] The test described below is used to examine the substancesaccording to the invention for potential side-effects with respect to aninduction of cytochrome P450 enzymes.

[0290] Examination of the Induction of Cytochrome P450 Enzymes in HumanLiver Cell Cultures:

[0291] At a cell density of 2.5×10⁵ cells, primary human hepatocyteswere cultivated between two layers of collagen in 24-well microtitreplates, at 37° C. and 5% CO₂, for 8 days. The cell culture medium waschanged daily.

[0292] After 48 hours in culture, the hepatocytes were treated for 5days with different concentrations of the test substances, compared tothe inductors rifampicin (50 μM) and phenobarbital (2 mM), each testbeing carried out twice. The final concentrations of the test substanceswere 0.1-10 μg/ml.

[0293] Using the cell cultures, the inductive effect of the testsubstances on the cytochrome (CYP) P450 enzymes 1A2, 2B6, 2C19 and 3A4was determined on day 8 by addition of the substrates 7-ethoxyresorufin(CYP1A2), [¹⁴C]S-mephenyloin (CYP2B6 and 2C19) and [¹⁴C]testosterone(CYP3A4). The inductive potential of the test substances was determinedusing the measured enzyme activities CYP1A2, 2B6, 2C19 and 3A4 oftreated cells compared to untreated cells.

[0294] The novel active compounds can be converted in a known mannerinto the customary formulations, such as tablets including coatedtablets, pills, granules, aerosols, syrups, emulsions, suspensions andsolutions, using inert, non-toxic, pharmaceutically suitable excipientsor solvents. In this case, the therapeutically active compound should ineach case be present in a concentration from approximately 0.5 to 90% byweight of the total mixture, i.e. in amounts which are sufficient inorder to achieve the dosage range indicated.

[0295] The formulations are prepared, for example, by extending theactive compounds with solvents and/or excipients, if appropriate usingemulsifying agents and/or dispersing agents, it being possible, forexample if the diluent used is water, to use organic solvents asauxiliary solvents, if appropriate.

[0296] Administrations carried out in a customary manner, preferablyorally, parenterally or topically, in particular perlingually orintravenously.

[0297] In the case of parenteral administration, solutions of the activecompounds using suitable liquid carrier materials can be employed.

[0298] In general, it has been found to be advantageous in the case ofintravenous administration to administer amounts of from about 0.001 to10 mg/kg, preferably from about 0.01 to 5 mg/kg, of body weight toachieve effective results, and in the case of oral administration thedose is about 0.01 to 25 mg/kg, preferably from 0.1 to 10 mg/kg, of bodyweight.

[0299] In spite of this, it may be necessary, if appropriate, to departfrom the amounts mentioned, namely depending on the body weight or onthe type of administration route, on the individual response towards themedicament, the manner of its formulation and the time or interval atwhich administration takes place. Thus, in some cases it may be adequateto manage with less than the above-mentioned minimum amount, while inother cases the upper limit mentioned must be exceeded. In the case ofthe administration of relatively large amounts, it may be advisable todivide these into several individual administrations over the course ofthe day.

[0300] Abbreviations:

[0301] Aloc-Cl allyl chloroformate

[0302] DCM dichloromethane

[0303] DIC N,N′-diisopropylcarbodiimide

[0304] DIEA diisopropylethylamine

[0305] DMF dimethylformamide

[0306] eq. equivalent(s)

[0307] sat. saturated

[0308] HOAc acetic acid

[0309] HOBt hydroxybenzotriazole

[0310] HONSu N-hydroxysuccinimide

[0311] MTP microtitre plate

[0312] PS- polystyrene-resin-

[0313] PyBOP benzotriazolyl-N-oxi-tris(dimethylamino)phosphoniumhexafluorophosphate

[0314] Rt retention time

[0315] RT room temperature

[0316] TBABH tetrabutylammonium borohydride

[0317] TFA trifluoroacetic acid

[0318] THF tetrahydrofuran

[0319] TMOF trimethyl orthoformate

[0320] General Procedure for the Reaction of Compounds of the Formula[A-1] with Compounds of the Formula [A-2] (GP 1):

[0321] 1.0 eq. of [A-1] are dissolved in dioxane (0.2 M solution), 2.5eq. of pyridine are added, the solution is cooled to 5° C. and 1.1 eq.of [A-2], in which Q is preferably chlorine, are added dropwise as a 1.0M solution. The mixture is stirred at 5° C. for another 30 min andcooling is then removed, and the mixture is stirred at room temperaturefor 16 h. The mixture is poured into H₂O and the precipitated product isfiltered off with suction, washed with H₂O and dried under high vacuum.

[0322] General Procedure for the Hydrogenation of Compounds of theFormula [A-3] (GP 2):

[0323] 0.14 mol of the compounds [A-3] is dissolved in 500 ml of DMF orethanol and, under argon, a suspension of 6.0 g of 10% of Pd—C is added.The mixture is then hydrogenated at a hydrogen pressure of 3 bar. Afterthe reaction has gone to completion (monitored by TLC or HPLC), the Pd—Ccatalyst is filtered off and the solvent is removed under reducedpressure. The crude products of the general formula [B-1] are reactedfurther without further purification.

[0324] General Procedure for the Sulphonylation of the Compounds of theGeneral Formula [B-1] (GP 3):

[0325] Under argon, 1.0 eq. of the compounds [B-1] is dissolved indioxane (0.2 M solution), and 2.5 eq. of pyridine are added. The mixtureis stirred at room temperature for 30 min, and 1.1 eq. of the compoundsof the general formula [C-1], in which Z is preferably chlorine,dissolved in dioxane (1.0 M solution) are then added and the mixture isstirred at room temperature for 16 h. The solution is then poured intoH₂O and extracted 3 times with DCM. The organic phase is washed withsat. NaHCO₃ solution, dried over Na₂SO₄ and filtered, and the solvent isremoved under reduced pressure. The residue [C-2] is dried under highvacuum and then reacted further without further purification.

[0326] General Procedure for the Synthesis of Compounds of the GeneralFormula [D-1] from Compounds of the General Formula [C-2] (GP 4):

[0327] The compounds of the formula [C-2] (1.0 eq.) are dissolved inethanol (0.1 M solution), hydroxylamine hydrochloride (1.5 eq.) andtriethylamine (1.6 eq.) are added to the solution and the solution isthen heated under reflux for 4 h and stirred at room temperature foranother 16 h. The solvent is removed under reduced pressure, the residueis taken up in ethyl acetate and extracted 3× with water, the organicphase is dried over MgSO₄ and filtered and the solvent is removed underreduced pressure. The residue [D-1] is dried under high vacuum.

[0328] General Procedure for the Reaction of the Compounds of theGeneral Formula [D-1] with Compounds [E-1] (GP 5):

[0329] 1.0 eq. of the compounds of the general formula [D-1], 1.05 eq.of carboxylic acid [E-1] and 1.1 eq. of PyBOP are initially charged inTHF (0.1 M solution), 1.1 eq. of N,N-diisopropylethylamine are added tothe suspension and the resulting solution is stirred at room temperaturefor 16 h. The mixture is then diluted with 10 ml of DCM and extracted ineach case once with 1 N HCl, sat. NaHCO₃ solution and sat. NaClsolution. The organic phase is dried over Na₂SO₄ and filtered and thesolvent is removed under reduced pressure. The crude product is directlyreacted further.

[0330] General Procedure for the Synthesis of a 1,2,4-Oxadiazole fromthe Crude Product Obtained According to GP 5 (GP 6):

[0331] 1.0 mmol of crude product, obtained according to GP 5, is takenup in 10 ml of DMF, and the solution is heated at 110° C. Once thereaction has gone to completion (monitored by TLC or HPLC, about 2-16h), the mixture is diluted with DCM and extracted twice with H₂O. Thecombined aqueous phases are extracted twice with DCM, the organic phasesare combined, dried over Na₂SO₄ and filtered and the solvent is removedunder reduced pressure. The resulting compounds of the general formula(I) are purified by silica gel chromatography (cyclohexane/ethylacetate) or by preparative HPLC.

[0332] General Procedures for Syntheses using Polymeric Supports:

[0333] General Procedure for the Synthesis of 1,3,4-Oxadiazolesaccording to Scheme 4:

[0334] The reactions according to Scheme 4 were carried out on apolymeric support using the IRORI system according to the “Split & Mix”method, known to the solid-phase chemist, employing 4 carbonylchlorides, 24 carboxylic acids and the two meta- or para-isomers of thephenylenediamine or sulphonyl chloride. Here, the first two steps werecarried out in a flask, the other steps in IRORI MiniKans (100 mg ofresin per can).

[0335] Synthesis of the Starting Resins (I) and (II) for the Syntheseson the Polymeric Support according to Scheme 4:

[0336] Reductive Amination of Formyl Resin (from Nova Biochem, 0.78mmol/g):

[0337] The formyl resin (1.0 eq.) is, in a flask, suspended in TMOF/DMF(100 ml per 12.5 g of resin), and the diamine (6.0 eq.) is added. Thesuspension is shaken at 40° C. for 16 h, and a freshly prepared solutionof TBABH (4.0 eq.) and HOAc (16.0 eq.) in DMF is then added. After 8 hat RT, the solvent is filtered off, and once more, reduction solution isadded to the resin. After a further 16 h at RT, the solvent is filteredoff with suction and the resin (I) is washed in each case 2× with ineach case 200 ml of 50% strength HOAc, DMT, THF and DCM and dried underhigh vacuum.

[0338] Sulphonylation of Polymer-Bound Phenylenediamine:

[0339] The resin (I) (1.0 eq.) is taken up in THF, and the sulphonylchloride (1.5 eq.) is added. The suspension is shaken at RT for 16 h,and the solvent is filtered off with suction. The resin (H) is thenwashed in each case 2× with in each case 100 ml of 50% strength HOAc,DMF, THF and DCM and dried under high vacuum.

[0340] Preparation of the Resin for the IRORI System:

[0341] The resins of type II are distributed as a suspension (per 3.0 gof resin: 30 ml of DMF/DCM 2:1 v/v) into in each case 96 MiniKans (1 mlsuspension per Kan) and washed in each case three times with DCM, andthe Kans are dried under reduced pressure.

[0342] Reaction Sequence (IRORI):

[0343] Acylation with Acid Chlorides:

[0344] The Kans are sorted and taken up in THF, 5.0 eq. of DIEA and 5.0eq. of acid chloride are added and the Kans are evacuated briefly andshaken at RT for 3 h. The reaction solutions are then separated off andthe Kans are combined and washed (in each case 2×50% strength HOAc, DMF,THF, DCM).

[0345] Hydrazide Synthesis:

[0346] The combined Kans are taken up in a mixture of 2 N NaOH/MeOH/THF(5:7:15 v/v), evacuated briefly and stirred at 50° C. for 5 h. The Kansare then washed (in each case 2×50% strength HOAc, DMF, THF, DCM) anddried under reduced pressure.

[0347] The Kans are then taken up in THF, 5 eq. of DIC and 10 eq. ofHONSu are added and the Kans are shaken at RT for 3 h. The Kans arefiltered off, washed 2× with THF and then once more taken up in THF, and3 eq. of hydrazine hydrate are added. After a further 3 h at RT, theKans are filtered off with suction and washed in each case 2× with 50%strength HOAc, DMF, THF and DCM.

[0348] Acylation with Carboxylic Acids/DIC/HOBt:

[0349] 3 eq. of DIC, 6 eq. of DIEA and 6 eq. of HOBt are added to thecarboxylic acids (3 eq.) in THF. After 60 min of activation at RT, thesolution is added to the Kans, which have been sorted beforehand, and isshaken at RT for 16 h. The Kans are then combined, washed (in each case2× with 50% strength HOAc, DoF, THF, DCM) and dried under reducedpressure.

[0350] Cyclization to the 1,3,4-Oxadiazole:

[0351] The combined Kans are taken up in DMF, DCI (10 eq.) is added andthe Kans are evacuated briefly and stirred at 110° C. for 48 h. The Kansare then washed (in each case 2× with 50% strength HOAc, DMF, THF, DCM)and dried under reduced pressure.

[0352] Cleavage from the Polymeric Support:

[0353] After sorting into IRORI cleavage blocks, the Kans are cut open,the resin is distributed into FlexChem blocks and the products arecleaved in a Deep-Well MTP using in each case 1.0 ml of TFA/DCM (1:1v/v) at RT for 45 min. The resin is washed with DCM and the solvent isevaporated.

[0354] General Procedure for the Synthesis of the 1,3,4-ThiadiazolesAccording to Scheme 5:

[0355] The synthesis is carried out by a mixed approach of solid-phasesynthesis and synthesis in solution.

[0356] Synthesis of the Monosulphonylated Phenylenediamine:

[0357] The phenylenediamine (1.0 eq.) is dissolved in TBF (0.4 Msolution), 1.0 eq. of sulphonyl chloride are added and the mixture isstirred at RT for 16 h. The mixture is then diluted with DCM andextracted 2× with water, the aqueous phases are reextracted 1× with DCMand the org. phases are combined, dried over Na₂SO₄ and concentratedusing a rotary evaporator. The crude product is reacted further withoutfurther purification.

[0358] Attachment to the Polymeric Support and Synthesis of theThiadiazole:

[0359] Reductive Amination of Formyl Resin (from Nova Biochem, 0.78mmol./g):

[0360] The formyl resin (1.0 eq.) is, in a flask, suspended in TMOF/DMF(100 ml per 12.5 g of resin), and the sulphonylated phenylenediamine(6.0 eq.) is added. The suspension is shaken at 40° C. for 16 h, and afreshly prepared solution of TBABH (4.0 eq.) and HOAc (16.0 eq.) in DMFis then added. After 8 h at RT, the solvent is filtered off, and oncemore, reduction solution is added to the resin. After a further 16 h atRT, the solvent is filtered off with suction and the resin is washed ineach case 2× with in each case 200 ml of 50% strength HOAc, DMF, THF andDCM and dried under high vacuum.

[0361] Acylation of the Resin:

[0362] In a syringe with PE fritt (from MultiSyntech), the resin issuspended in THF, and 3.0 eq. of DIEA and 3.0 eq. of carbonyl chlorideare added. The suspension is shaken at RT for 3 h and then filtered offwith suction, and the resin is washed in each case 2× with 50% strengthHOAc, DMF, THF and DCM.

[0363] Hydrazide Synthesis:

[0364] In a syringe with PE fritt (from MultiSyntech), the resin istaken up in a mixture of 2 N NaOH/MeOH/THF (5:7:15 v/v), stirred at 50°C. for 5 h and then washed (in each case 2× with 50% strength HOAc, DMF,THF, DCM). The resin is then taken up in THF, 5 eq. of DIC and 10 eq. ofHONSu are added and the mixture is shaken at RT for 3 h. The resin isfiltered off, washed 2× with THF and then once more taken up in THF, and3 eq. of hydrazine hydrate are added. After a further 3 h at RT, theresin is filtered off with suction and washed (in each case 2× with 50%strength HOAc, DMF, THF, DCM).

[0365] Acylation of the Hydrazide with Carboxylic Acids/DIC/HOBt:

[0366] 3 eq. of DIC, 6 eq. of DIEA and 6 eq. of HOBt are added to thecarboxylic acid (3 eq.) in THF. After 6 min of activation at roomtemperature, the solution is added to the resin (1 ml per 100 mg ofresin), and the mixture is shaken at RT for 16 h. The resin is thenfiltered off with suction and washed (in each case 2× with 50% strengthHOAc, DMF, THF, DCM). The LC-MS of the cleaved sample shows that thedouble bond of the allyloxycarbonyl group is hydrogenated in thisreaction.

[0367] Thiadiazole Synthesis:

[0368] The resin is initially charged in dioxane (1 ml per 100 mg ofresin), 5.0 eq. of Lawesson's reagent are added and the mixture isstirred at 90° C. for 3 h. The resin is then filtered off with suctionand washed in each case 2× with DMF, 50% strength HOAc, DMF, THF andDCM.

[0369] Cleavage from the Polymeric Support, Removal of the CarbonateProtective Group and Synthesis of the Amide:

[0370] The resin is treated with TFA/DCM (1:1 v/v, 1 ml per 100 mg ofresin) and, after 45 min, filtered off and washed with DCM (samevolume). TFA and DCM are removed under reduced pressure and the residueis taken up in ethanol/2.5 N NaOH (1:1 v/v, 0.5 M solution), stirred at75° C. for 16 h, diluted with DCM and extracted 2× with water, theaqueous phase is adjusted to pH 7 using 1 N HCl and extracted 3× withDCM, all org. phases are combined, washed 2× with water, dried overNa₂SO₄ and concentrated using a rotary evaporator. The residue is takenup in THF, 1.05 eq. of DEA and 1.05 eq. of acid chloride are added andthe mixture is shaken at RT for 16 h. Volatile components are thenremoved under reduced pressure and the product is isolated bypreparative HPLC.

[0371] Starting Materials:

EXAMPLE I

[0372] 1-Methyl-N-(3-nitrophenyl)-cyclopropan Amide

[0373] This compound is prepared according to GP 1 from 80.0 g of3-nitroaniline.

[0374] Yield: 107 g (81% of theory)

EXAMPLE II 3-Fluor-2,2-dimethyl-N-(3-aminophenyl)-propanamide

[0375]

[0376] This compound is prepared according to GP 1 and GP 2 from3-nitroaniline, without purification of the intermediate.

[0377] Yield: 85% of theory (over 2 steps)

EXAMPLE III

[0378] 1-Methyl-N-(3-aminophenyl)-cyclopropanamide

[0379] This compound is prepared according to GP 2 from 107 g of thecompound from Example 1.

[0380] Yield: 80 g (87% of theory)

EXAMPLE IV

[0381] 3-Fluoro-2,2-dimethyl-N-(3-{[(4-methylphenyl)sulphonyl]amino}phenyl)-propanamide

[0382] This compound is prepared according to GP 3 from 18.68 g of thecompound from Example II.

[0383] Yield: 19.96 g (78% of theory)

EXAMPLE V

[0384]N-{3-[({4-[Amino(hydroxyimino)methyl]phenyl}sulphonyl)amino]phenyl}-3-fluoro-2,2-dimethylpropanamide

[0385] This compound is prepared according to GP 4 from 10.0 g of thecompound from Example IV.

[0386] Yield: 10.5 g (97% of theory)

EXAMPLE VI

[0387]N-(3-{[(4-Cyanophenyl)sulphonyl]amino}phenyl)-1-methylcyclopropanecarboxamide

[0388] This compound is prepared according to GP 3 from 90 g of thecompound from Example I.

[0389] Yield: 150 g of crude product (quant.)

[0390] HPLC: Rt=2.87 min (HPLC method/instrument 9)

EXAMPLE VII

[0391]N-{3-[({4-[Amino(hydroxyimino)methyl]phenyl}sulphonyl)amino]phenyl}-1-methyl-cyclopropanecarboxamide

[0392] This compound is prepared according to GP 3 from 168 g of thecompound from Example VI (as crude product).

[0393] Yield: 118 g (57% of theory)

[0394] HPLC: Rt=2.7 min (HPLC method/instrument 5)

[0395] MW 388.45; m/z found: 389

EXAMPLE VIII

[0396] 2-Aminoacetyl-picoline

[0397] 25.0 g (0.23 mol) of 6-aminopicoline are dissolved in 250 ml ofacetic acid, and 47.2 g (0.46 mol) of acetic anhydride are added withstirring and ice-cooling. Initially, the mixture is stirred withice-cooling for another 30 min, and the ice bath is then removed andstirring is continued at room temperature for 16 h. The clear solutionis then concentrated under reduced pressure. The oily residue iscrystallized in an ice bath and the crystals are dried under reducedpressure.

[0398] Yield: 28 g (80.6% of theory)

[0399]¹H-NMR (200 MHz, DMSO-d₆): δ=10.41 (s, 1H), 7.87 (d, 1H), 7.63 (t,1H), 6.93 (d, 1H), 2.39 (s, 3H), 2.06 (s, 3H).

EXAMPLE IX

[0400] 2-Aminoacetyl-picolinic Acid

[0401] 31.0 g (0.21 mol) of 2-aminoacetylpicoline are dissolved in 310ml of water and heated at 75° C., and 60.0 g (0.38 mol) of potassiumpermanganate are added a little a time over a period of 3 h such thatthe violet colour disappears again in each case. The mixture is stirredat 75° C. for another 5 h, and the hot reaction mixture is thenfiltered. The aqueous phase is extracted four times with dichloromethaneand then acidified to pH 4 using 1 N hydrochloric acid. The precipitateis filtered off, washed with 0.1 N hydrochloric acid and dried underreduced pressure.

[0402] Yield: 15.5 g (42% of theory)

[0403] HPLC: Rt=1.11 min (HPLC method/instrument 3)

[0404] MW 180.16; m/z found: 181

[0405]¹H-NMR (200 MHz, DMSO-d₆): δ=13.23 (br s, 1H), 10.81 (s, 1H), 8.28(d, 1H), 7.94 (t, 1H), 7.73 (dd, 1H), 2.12 (s, 3H).

WORKING EXAMPLES

[0406] The 1,2,4-oxadiazoles attached in the 3-position shown in theworking examples below were prepared from compounds of type Example Vaccording to GP 5 and GP6.

Example 1

[0407]3-Fluoro-2,2-dimethyl-N-{3-[({4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]phenyl}-sulphonyl)amino]phenyl}propanamide

[0408] 5.93 g (45.92 mmol) of N,N-diisopropylethylamine, 5.65 g (45.92mmol) of picolinic acid and 23.89 g (45.92 mmol) of PyBOP are initiallycharged in 70 ml of THF, the mixture is stirred at room temperature for30 min, 17.05 g (41.74 mmol) of amidoxime from Example V are then addedand the solution is stirred at room temperature for 16 h. The reactionmixture is concentrated under reduced pressure, the residue is taken upin 50 ml of DMF and the solution is stirred at 110° C. for 4 h. Themixture is then diluted with 300 ml of DCM, and the organic phase isextracted three times with in each case 200 ml of 2 N H₂SO₄ and oncewith sat. NaHCO₃ solution. The organic phase is dried over Na₂SO₄ andfiltered, and the solvent is removed under reduced pressure (43.5 g ofcrude product). The product is purified by silica gel chromatographyusing cyclohexane/ethyl acetate (6:4 v/v) and, after purification,stirred with cyclohexane, and the solid is filtered off with suction anddried under reduced pressure.

[0409] Yield: 12.59 g (61% of theory) of a white solid

[0410] m.p.: 178.9° C.

[0411] MW 495.53; m/z found: 496

[0412] HPLC Rt: 4.38 min. (LC method/instrument 3)

[0413]¹H-NMR (300 MHz, DMSO): δ=1.20 (s, 3H), 1.21 (s, 3H), 4.48 (d,2H), 6.81 (d, 1H), 7.14 (t, 1H), 7.31 (d, 1H), 7.58 (s, 1H), 7.71-7.78(m, 1H), 7.99 (d, 2H), 8.09-8.18 (m, 1H), 8.27 (d, 2H), 8.34 (d, 1H),8.86 (d, 1H), 9.35 (s, 1H), 10.43 (s, 1H).

Example 2

[0414]N-(3-{[(4-{5-[3-(Dimethylamino)phenyl]-1,2,4-oxadiazol-3-yl}phenyl)sulphonyl]-amino}phenyl)-1-methylcyclopropanecarboxamide

[0415] MW 517.61; m/z found: 518

[0416] HPLC Rt: 3.25 min. (HPLC method/instrument: 3)

[0417]¹H-NMR (300 MHz, DMSO): δ=0.54-0.64 (m, 2H), 1.00-1.09 (m, 2H),1.36 (s, 3H), 3.00 (s, 6H), 6.79 (d, 1H), 7.02-7.50 (m, 6H), 7.57 (t,1H), 7.97 (d, 2H), 8.24 (d, 2H), 9.15 (s, 1H), 10.34 (s, 1H).

Example 3

[0418]1-Methyl-N-{3-[({4-[5-(2-pyridinyl)-1,2,4-oxadiazol-3-yl]phenyl}sulphonyl)-amino]phenyl}cyclopropanecarboxamide

[0419] 20.0 g (51.59 mmol) of the appropriate amidoxime, 6.66 g (54.06mmol) of picolinic acid and 29.47 g (56.66 mmol) of PyBOP are initiallycharged in 60 ml of THF, 7.32 g (56.66 mmol) ofN,N-diisopropylethylamine are added at room temperature to thesuspension and the resulting clear solution is stirred at roomtemperature for 16 h. The mixture is then diluted with 250 ml of DCM andextracted in each case once with in each case 250 ml of 1 N HCl, sat.NaHCO₃ solution and sat. NaCl solution. The organic phase is dried overNa₂SO₄ and filtered, and the solvent is removed under reduced pressure.The crude product (25.41 g) is taken up in 250 ml of DMF, and thesolution is stirred at 110° C. for 2.5 h. The mixture is then dilutedwith 250 ml of DCM, and the organic phase is extracted twice with ineach case 250 ml of H₂O. The combined aqueous phases are extracted twicewith in each case 250 ml of DCM, the organic phases are combined, driedover Na₂SO₄ and filtered and the solvent is removed under reducedpressure (43.5 g of crude product). The product is purified bychromatography on silica gel 60 using cyclohexane/ethyl acetate 1:1 v/v.

[0420] Yield: 18.35 g (75% of theory) of a white solid

[0421] m.p.: 202° C.

[0422] MW 475.53; m/z found: 476

[0423] HPLC Rt: 4.0 min. (HPLC method/instrument: 6)

[0424]¹H-NMR (200 Mz, DMSO): δ=0.55-0.64 (m, 2H), 1.00-1.10 (m, 2H),1.36 (s, 3H), 6.78 (d, 1H), 7.11 (t, 1H), 7.27 (d, 1H), 7.57 (s, 1H),7.70-7.79 (m, 1H), 8.08 (d, 2H), 8.09-8.19 (m, 1H), 8.26 (d, 2H), 8.34(d, 1H), 8.87 (d, 1H), 9.17 (s, 1H), 10.38 (s, 1H).

Example 4

[0425]N-{3-[({4-[5-(2-Amino-1,3-thiazol-4-yl)-1,2,4-oxadiazol-3-yl])phenyl}sulphonyl)-amino]phenyl}-1-methylcyclopropanecarboxamide

[0426] MW 496.57; m/z found: 497

[0427] HPLC Rt: 2.508 min. (HPLC method/instrument: 8)

[0428]¹H-NMR (200 MHz, DMSO): δ=0.54-0.64 (m, 2H), 1.00-1.09 (m, 2H),1.36 (s, 3H), 6.78 (d, 1H), 7.12 (t, 1H), 7.28 (d, 1H), 7.52 (s, 1H),7.57 (s, 1H), 7.82 (s, 1H), 7.95 (d, 2H), 8.19 (d, 2H), 9.18 (s, 1H),10.38 (s, 1H).

Example 5

[0429]1-Methyl-N-{3-[({4-[5-(6-methyl-2-pyridinyl)-1,2,4-oxadiazol-3-yl]phenyl}-sulphonyl)amino]phenyl}cyclopropanecarboxamide

[0430] MW 489.55; m/z found: 490

[0431] HPLC Rt: 4.76 min. (HPLC method/instrument: 6)

[0432]¹H-NMR (200 MHz, DMSO): δ=0.54-0.63 (m, 2H), 1.00-1.09 (m, 2H),1.36 (s, 3H), 2.61 (s, 3H), 6.77 (d, 1H), 7.10 (t, 1H), 7.26 (d, 1H),7.50-7.65 (m, 2H), 7.92-8.06 (m, 3H), 8.14 (d, 1H), 8.25 (d, 2H), 9.17(s, 1H), 10.39 (s, 1H).

Example 6

[0433]1-Methyl-N-{3-[({4-[5-(3-methyl-1H-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]phenyl}-sulphonyl)amino]phenyl}cyclopropanecarboxamide

[0434] MW 478.53; “nIz found: 479

[0435] HPLC Rt: 3.77 min. (HPLC method/instrument: 6)

[0436]¹H-NMR (200 MHz, DMSO): δ=0.54-0.65 (m, 2H), 0.99-1.12 (m, 2H),1.36 (s, 3H), 2.34 (s, 3H), 6.77 (d, 1H), 7.10 (t, 1H), 7.25 (d, 1H),7.54 (s, 1H), 7.95 (d, 2H), 8.20 (d, 2H), 9.16 (s, 1H), 10.38 (s, 1H),13.58 (s, 1H).

Example 7

[0437]1-Methyl-N-{3-[({4-[5-(1,3-thiazol-4-yl)-1,2,4-oxadiazol-3-yl]phenyl}sulphonyl)-amino]phenyl}cyclopropanecarboxamide

[0438] MW 481.56; m/z found: 482

[0439] HPLC Rt: 2.689 min. (HPLC method/instrument: 8)

[0440]¹H-NMR (300 Mz, DMSO): δ=0.55-0.63 (m, 2H), 1.01-1.09 (m, 2H),1.36 (s, 3H), 6.77 (d, 1H), 7.12 (t, 1H), 7.28 (d, 1H), 7.58 (s, 1H),7.98 (d, 2H), 8.24 (d, 2H), 8.95 (d, 1H), 9.19 (s, 1H), 9.40 (d, 1H),10.39 (s, 1H).

Example 8

[0441]N-{3-[({4-[5-(1,5-Dimethyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl}-sulphonyl)amino]phenyl}-1-methylcyclopropanecarboxamide

[0442] MW 492.56; m/z found: 493

[0443] HPLC Rt: 2.788 min. (HPLC method/instrument: 8)

[0444]¹H-NMR (200 MHz, DMSO): δ=0.53-0.64 (m, 2H), 0.97-1.12 (m, 2H),1.36 (s, 3H), 2.35 (s, 3H), 3.89 (s, 3H), 6.77 (d, 1H), 6.85 (s, 1H),7.11 (t, 1H), 7.27 (d, 1H), 7.56 (s, 1H), 7.95 (d, 2H), 8.21 (d, 2H),9.18 (s, 1H), 10.38 (s, 1H).

Example 9

[0445]1-Methyl-N-{3-[({4-[5-(5-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-3-yl]phenyl}-sulphonyl)amino]phenyl}cyclopropanecarboxamide

[0446] MW 478.53; m/z found: 479

[0447] HPLC Rt: 2.614 min. (HPLC method/instrument: 8)

[0448]¹H-NMR (300 MHz, DMSO): δ=0.57-0.63 (m, 2H), 1.01-1.08 (m, 2H),1.36 (s, 3H), 2.34 (s, 3H), 6.75-6.80 (m, 2H), 7.10 (t, 1H), 7.26 (d,1H), 7.54 (s, 1H), 7.96 (d, 2H), 8.20 (d, 2H), 9.16 (s, 1H), 10.38 (s,1H), 13.58 (s, 1H).

Example 10

[0449]N-{3-[({4-[5-(1-Isoquinolinyl)-1,2,4-oxadiazol-3-yl]phenyl}sulphonyl)-amino]phenyl}-1-methylcyclopropanecarboxamide

[0450] MW 525.59; m/z found: 526

[0451] HPLC Rt: 4.34 min. (HPLC method/instrument: 5)

[0452]¹H-NMR (200 MHz, DMSO): δ=0.54-0.67 (m, 2H), 0.99-1.11 (m, 2H),1.36 (s, 3H), 6.80 (d, 1H), 7.12 (t, 1H), 7.28 (d, 1H), 7.58 (s, 1H),7.86-7.99 (m, 2H), 8.01 (d, 2H), 8.15-8.29 (m, 1H), 8.26 (d, 1H), 8.36(d, 2H), 8.82 (d, 1H), 9.18 (s, 1H), 9.26-9.36 (m, 1H), 10.41 (s, 1H).

Example 11

[0453]1-Methyl-N-{3-[({4-[5-(2-methyl-1,3-thiazol-4-yl)-1,2,4-oxadiazol-3-yl]phenyl}-sulphonyl)amino]phenyl}cyclopropanecarboxamide

[0454] MW 495.58; m/z found: 496

[0455] HPLC Rt: 2.813 min. (HPLC method/instrument: 8)

[0456]¹H-NMR (200 MHz, DMSO): δ=0.55-0.63 (m, 2H), 1.00-1.09 (m, 2H),1.36 (s, 3H), 2.78 (s, 3H), 6.78 (d, 1H), 7.12 (t, 1H), 7.28 (d, 1H),7.58 (s, 1H), 7.97 (d, 2H), 8.23 (d, 2H), 8.73 (s, 1H), 9.19 (s, 1H),13.39 (s, 1H).

Example 12

[0457]N-(3-{[(4-{5-[2-(Aminomethyl)-1,3-thiazol-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)-sulphonyl]amino}phenyl)-1-methylcyclopropanecarboxamide

[0458] MW 510.60, m/z found: 511

[0459] HPLC Rt: 1.71 min. (HPLC method/instrument: 8)

[0460]¹H-NMR (200 MHz, DMSO): δ=0.54-0.64 (m, 2H), 0.99-1.09 (m, 2H),1.36 (s, 3H), 4.09 (s, 2H), 6.77 (d, 1H), 7.11 (t, 1H), 7.27 (d, 1H),7.56 (s, 1H), 7.96 (d, 2H), 8.22 (d, 2H), 8.75 (s, 1H), 9.18 (s, 1H).

Example 13

[0461]3-Fluoro-2,2-dimethyl-N-[4-({[3-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl]sulphonyl}-amino)phenyl]propanamide

[0462] MW 494.54; m/z found: 495

[0463] HPLC Rt: 4.8 min. (HPLC method/instrument: 3)

[0464]¹H-NMR (300 MHz, DMSO): δ=1.17 (s, 6H), 4.44 (d, 2H), 7.04 (d,2H), 7.48 (d, 2H), 7.63-7.81 (m, 4H), 7.90 (d, 1H), 8.22 (d, 2H), 8.30(d, 1H), 8.45 (s, 1H), 10.31 (s, 1H).

[0465] Further 1,2,4-oxadiazole derivatives which are attached viaposition 3 and were prepared in accordance with the processes accordingto the invention are listed in Table 2: Ex- am- HPLC HPLC m/z ple R₁method/ found No. Structure MW [min] instrument [M + H] 14

525.59 5.03 6 526 15

476.51 2.63 8 477 16

517.61 4.28 3 518 17

475.53 3.90 6 476 18

554.42 4.80 3 554 (79Br) 19

521.60 3.14 8 522 20

495.53 4.34 3 496 21

491.53 3.40 6 492 22

495.53 4.13 3 496 23

494.54 4.95 3 495 24

482.54 2.72 8 483 25

463.52 2.83 8 464 26

501.56 4.41 3 502 27

501.56 4.96 3 502 28

475.53 2.66 8 476 29

475.53 2.70 8 476 30

492.00 4.46 3 493 31

495.53 4.44 3 496 32

554.42 4.75 3 555 33

475.53 3.89 6 476 34

496.57 3.65 5 497 35

496.52 4.30 3 497 36

496.52 4.33 3 497 37

529.58 2.68 8 530 38

464.50 2.36 8 465 39

496.57 2.52 8 497 40

516.58 4.19 3 517 41

496.57 3.59 5 497 42

509.54 2.69 8 510 43

491.53 3.98 3 492 44

474.54 4.55 6 475 45

495.53 4.17 3 496 46

495.53 4.49 3 496 47

475.52 2.63 8 476 48

494.54 4.87 3 495 49

492.00 4.10 3 493 50

495.53 4.18 3 496 51

496.52 4.32 3 497 52

496.52 4.35 3 497 53

475.52 2.60 8 476 54

555.61 4.64 6 556

[0466] Further 1,3,4-oxadiazole derivatives attached via position 5 andprepared according to the processes according to the invention arelisted in Table 3: Exam- ple m/z found HPLC R₁ HPLC method/ No.Structure MW [M + H] [min] instrument 55

494.55 495 4.15 6 56

517.61 515 4.26 6 57

474.54 475 4.17 6 58

517.61 518 4.35 6 59

537.62 538 4.3 6 60

511.00 511, 513 (35Cl, 37Cl) 4.31 6 61

476.58 477 4.23 6 62

519.63 520 4.38 6 63

519.63 520 4.44 6 64

517.61 518 4.33 6 65

475.53 476 3.66 6 66

554.07 554, 556 (35Cl, 37Cl) 4.48 6 67

494.55 495 4.20 6 68

537.62 538 4.37 6 69

476.56 477 4.27 6 70

474.54 475 4.17 6 71

475.53 476 3.60 6 72

537.62 538 4.35 6 73

475.53 475 3.69 6 74

475.53 476 3.54 6 75

554.07 554, 556 (35Cl, 37Cl) 4.47 6 76

474.54 475 4.13 6 77

519.63 520 4.43 6 78

511.99 512, 514 (35Cl, 37Cl) 3.84 6 79

494.55 495 4.2 6 80

476.56 477 4.28 6 81

475.53 476 3.6 6 82

511.00 511, 513 (35Cl, 37Cl) 4.32 8 83

517.61 518 4.29 6 84

477.55 478 3.77 6 85

476.52 477 3.56 6 86

495.54 496 3.71 6 87

475.53 476 3.55 6 88

511.99 512, 514 (35Cl, 37Cl) 3.78 6 89

475.53 476 3.55 6 90

537.62 538 4.32 6 91

476.52 477 3.57 6 92

494.55 495 4.17 6 93

495.54 496 3.6 6 94

495.54 496 3.64 6 95

477.55 478 3.71 6 96

476.56 477 4.24 6 97

476.52 477 3.51 6 98

511.99 512, 514 (35Cl, 37Cl) 3.78 6 99

475.53 476 3.48 6 100

477.55 478 3.8 6 101

511.99 512, 514 (35Cl, 37Cl) 3.87 6 102

495.54 498 3.54 6 103

495.54 496 3.64 6 104

519.63 520 4.4 6 105

475.53 476 3.55 6 106

477.55 478 3.71 6 107

477.55 478 3.67 6 108

478.53 479 3.67 6 109

512.98 513, 515 (35Cl, 37Cl) 3.76 6 110

496.52 497 3.60 6 111

511.99 512, 514 (35Cl, 37Cl) 3.73 6 112

495.54 496 3.73 6 113

495.54 496 3.6 6 114

495.52 497 3.57 6 115

477.55 478 3.61 6 116

511.99 512, 514 (35Cl, 37Cl) 3.74 6 117

495.54 496 3.59 6 118

478.53 479 3.68 6 119

475.53 476 3.5 6 120

478.53 479 3.64 6 121

477.55 478 3.66 6 122

477.55 478 3.66 6 123

477.55 478 3.67 6 124

495.54 496 3.60 6 125

496.52 497 3.61 6 126

476.52 477 3.51 6 127

511.99 512, 514 (35Cl, 37Cl) 3.86 6 128

495.54 496 3.55 6 129

496.52 497 3.56 6 130

477.55 478 3.62 6

Example 131

[0467]1-Methyl-N-{4-[({3-[5-(2-pyridinyl)-1,3,4-thiadiazol-2-yl]phenyl}sulphonyl)amino]phenyl}cyclopropanecarboxamide

[0468] MW 491.59; m/z found: 490 (neg. ESI)

[0469] HPLC Rt: 4.03 min. (HPLC method/instrument: 5)

[0470]¹H-NMR (400 MHz, DMSO): δ=0.56-0.59 (m, 2H), 1.01-1.06 (m, 2H),1.34 (s, 3H), 7.04 (d, 2H), 7.48 (d, 2H), 7.63-7.65 (m, 1H), 7.76 (t,3H), 7.88 (d, 1H), 8.09 (dt, 1H), 8.26 (dt, 1H), 8.34 (d, 1H), 8.44 (t,1H), 8.75-8.77 (m, 1H), 10.10 (s, 1H), 10.27 (s, 1H).

Example 132

[0471]N-(3-{[(4-{5-[6-(Acetylamino)-2-pyridinyl]-1,2,4-oxadiazol-3-yl}phenyl)sulphonyl]-amino}phenyl)-1-methylcyclopropanecarboxamide

[0472] 8.1 g (20.85 mmol) of amidoxime from Example VII are initiallycharged in 50 ml of THF, 4.13 g (22.94 mmol) of 2-aminoacetylpicolinicacid (Example DC) and 16.28 g (31.28 mmol) of PyBOP are then added, and2.96 g (22.94 mmol) of N,N-diisopropylethylamine are then addeddropwise. The mixture is stirred at room temperature for 16 h, and thereaction mixture is then concentrated under reduced pressure, taken upin dichloromethane and washed successively, in each case once, with 1 Nhydrochloric acid and sat. sodium chloride solution. The organic phaseis dried over sodium sulphate, filtered and concentrated under reducedpressure. The residue (8.26 g) is dissolved in 75 ml ofN,N-dimethylformamide and stirred at 115° C. for 4 h. After cooling, 200ml of ethyl acetate are added and the mixture is washed 1× with 1 Nhydrochloric acid, 1× with sat. sodium chloride solution, 2× with sat.sodium bicarbonate solution and 1× with sat. sodium chloride solution.During washing, crystallization sets in in the organic phase.Accordingly, the organic phase is allowed to stand for 30 min and theprecipitated crystals are filtered off with suction and washed withmethanol [1. fraction, yield: 5.04 g (23% of theory)]. The mother liquoris dried over sodium sulphate, filtered and concentrated using a rotaryevaporator. Stirring with dichloromethane gives two further fractions ofcrystalline product [fraction 2, yield: 3.5 g (16% of theory); fraction3, yield: 1.1 g (5% of theory)]. The remaining mother liquor containsmore product which can be purified chromatographically [yield: 1.01 g(5% of theory)].

[0473] HPLC: Rt=4.42 min (HPLC method/instrument 3)

[0474] MW 550.59; m/z found: 551

[0475]¹H-NMR (200 MHz, DMSO-d₆): δ=11.00 (s, 1H); 10.41 (s, 1H); 9.18(s, 1H); 8.40 (dd, 1H); 8.24 (d, 2H); 8.14-9.97 (m, 4H); 7.57 (t, 1H);7.27 (d, 1H); 7.12 (t, 1H); 6.78 (d, 1H); 2.15 (s, 3H); 1.37 (s, 3H);1.08-1.03 (m, 2H); 0.62-0.57 (m, 2H).

Example 133

[0476]N-(3-{[(4-{5-[6-(Acetylamino)-2-pyridinyl]-1,2,4-oxadiazol-3-yl}phenyl)sulphonyl]-amino}phenyl)-3-fluoro-2,2-dimethylpropanamide

[0477] 7.80 g (19.1 mmol) of the amidoxime from Example V are initiallycharged in 100 ml of THE, 3.78 g (21.0 mmol) of 2-aminoacetylpicolinicacid and 14.91 g (28.6 mmol) of PyBOP are then added, and 2.71 g (21.0mmol) of N,N-diisopropylethylamine are finally added dropwise. Themixture is stirred at 40° C. for 16 h and the reaction mixture is thenconcentrated under reduced pressure, taken up in ethyl acetate andwashed successively, in each case twice, with 1 N hydrochloric acid andsat. sodium chloride solution. The organic phase is dried over sodiumsulphate, filtered and concentrated under reduced pressure. The productis purified by filtration through silica gel 0.60 using the mobile phaseethyl acetate. The resulting product (9.9 g) is dissolved in 90 ml ofN,N-dimethylformamide and stirred at 115° C. for 4 h. After cooling, thesolvent is removed under reduced pressure, 200 ml of ethyl acetate areadded and the mixture is washed 1× with 1 N hydrochloric acid, 1× withsat. sodium chloride solution, 2× with sat. sodium bicarbonate solutionand 1× with sat. sodium chloride solution. The organic phase is driedover sodium sulphate and the solvent is then removed. Duringconcentration, a precipitate is formed, and the suspension is thendiluted with dichloromethane and the precipitate is separated off andwashed with dichloromethane.

[0478] Yield: 5.4 g (55% of theory)

[0479] HPLC: Rt=4.44 min (HPLC method/instrument 3)

[0480] MW 552.58; m/z found: 553

[0481]¹H-NMR (200 MHz, DMSO-d₆): δ=10.99 (s, 1H); 10.43 (s, 1H); 9.36(s, 1H); 8.40 (dd, 1H); 8.25 (d, 2H); 8.13-7.98 (m, 4H); 7.59 (t, 1H);7.30 (d, 1H); 7.15 (t, 1H); 6.81 (d, 1H); 4.48 (d, 1H); 2.16 (s, 3H);1.21 (s, 6H).

Example 134

[0482]N-{3-[({4-[5-(6-Amino-2-pyridinyl)-1,2,4-oxadiazol-3-yl]phenyl}sulphonyl)amino]-phenyl}-1-methylcyclopropanecarboxamide

[0483] 15 g (28.16 mmol) of the compound from Example 132 are suspendedin 370 ml of ethanol, and 279 ml (281.7 mmol) of 1 N aqueous sodiumhydroxide solution are added. The mixture is stirred at 45° C. for 5 h(the suspension dissolves slightly), and the mixture is then, in an icebath, adjusted to pH=5 using 1 N hydrochloric acid, and the precipitatedcrystals are filtered off, washed with water and ethanol and dried at80° C. under high vacuum for 16 h.

[0484] Yield: 12 g (85.5% of theory)

[0485] HPLC: Rt=4.06 min (HPLC method/instrument 3)

[0486] MW 490.54; m/z found: 491

[0487]¹H-NMR (200 MHz, DMSO-d₆): δ=10.40 (s, 1H); 9.15 (s, 1H); 8.21 (d,2H); 7.96 (d, 2H); 7.68-7.43 (m, 3H); 7.25 (d, 1H); 7.10 (t, 1H); 6.76(t, 2H); 6.56 (d, 2H); 1.36 (s, 3H); 1.08-1.03 (s, 2H); 0.62-0.57 (m,2H).

Example 135

[0488]N-{3-[({4-[5-(6-Amino-2-pyridinyl)-1,2,4-oxadiazol-3-yl]phenyl}sulphonyl)amino]-phenyl}-3-fluoro-2,2-dimethylpropanamide

[0489] 19.3 g (34.9 mmol) of the compound from Example 133 are taken upin 290 ml of a mixture of water/conc. hydrochloric acid (1:1 v/v), andthe suspension is stirred at 100° C. for 4 h. The suspension is thenfiltered, the filter cake is stirred between sat. sodium bicarbonatesolution and ethyl acetate, the organic phase is separated off andconcentrated using a rotary evaporator and the crude product is purifiedchromatographically [silica gel 60, mobile phase toluene/acetone (8:2v/v)]. To remove adhering residual solvent, the clean fractions arecombined (6.8 g), dissolved, at 0° C., in 130 ml of 1 N aqueous sodiumhydroxide solution (turbid solution), and this solution is acidified topH=5 using 1 N hydrochloric acid. The precipitate is filtered off,washed with water and dried under high vacuum.

[0490] Yield: 6.4 g (36% of theory)

[0491] HPLC: Rt=4.09 min (HPLC method/instrument 3)

[0492] MW 510.55; m/z found: 511

[0493]¹H-NMR (500 MHz, DMSO-d₆): δ=10.42 (s, 1H); 9.33 (s, 1H); 8.21 (d,2H); 7.97 (d, 2H); 7.64 (t, 1H); 7.53 (s, 1H); 7.45 (d, 1H); 7.27 (d,1H); 7.12 (t, 1H); 6.78 (d, 1H); 6.73 (d, 1H); 6.57 (s, 2H); 4.48 (d,2H); 1.21 (s, 6H).

Example 136

[0494] Ethyl({6-[3-(4-{[(3-{[(1-methylcyclopropyl)carbonyl]amino}phenyl)amino]-sulphonyl}-phenyl)-1,2,4-oxadiazol-5-yl]-2-pyridinyl}amino)(oxo)-acetate

[0495] Under argon, 400 mg (0.82 mmol) of the compound from Example 134are dissolved in 12 ml of dichloromethane, and 70 mg (0.09 mmol) ofpyridine and 150 mg (1.1 mmol) of monoethyl oxalyl chloride are addedwith stirring. The solution is stirred at room temperature for another30 min. The reaction mixture is then added to 25 ml of pH 7 buffer, theaqueous phase is extracted three times with dichloromethane and thecombined organic phases are washed in each case twice with sat. sodiumchloride solution, sodium bicarbonate solution and sat. sodium chloridesolution. The organic phase is separated off, dried over sodium sulphateand concentrated under reduced pressure. The crude product is purifiedby chromatography on silica gel 60 using the mobile phase toluene/ethylacetate (1:1 v/v).

[0496] Yield: 349 mg (72% of theory)

[0497] HPLC: Rt=4.57 min (HPLC method/instrument 3)

[0498] MW 590.61; m/z found: 591

[0499]¹H-NMR (200 MHz, DMSO-d₆): δ=11.41 (s, 1H); 10.42 (s, 1H); 9.20(s, 1H); 8.28-8.16 (m, 6H); 8.00 (d, 1H); 7.60 (s, 1H); 7.28 (d, 1H);7.13 (t, 1H); 6.79 (d, 1H); 4.32 (q, 2H); 1.37-1.29 (m, 6H); 1.08-1.03(m, 2H); 0.63-0.58 (m, 2H).

Example 137

[0500]({6-[3-(4-{[(3-{[(1-Methylcyclopropyl)carbonyl]amino}phenyl)amino]sulphonyl}-phenyl)-1,2,4-oxadiazol-5-yl]-2-pyridinyl}amino)(oxo)-aceticAcid

[0501] 152 mg (0.26 mmol) of the compound from Example 136 are taken upin 7.5 ml of dioxane, and 0.75 ml (0.75 mmol) of 1 N aqueous sodiumhydroxide solution is added. The mixture is stirred at room temperaturefor 16 h and then carefully acidified to pH=7 using 1 N hydrochloricacid, and the solvent is removed under reduced pressure. The crudeproduct is purified by preparative HPLC (CromSil C18, 250×30 mm, flowrate 50 ml/min, runtime 35 min, detection at 254 nm, gradient 10%acetonitrile @ 3 min->90% acetonitrile @ 31 min->90% acetonitrile @ 34min->10% acetonitrile @ 34.01 min).

[0502] Yield: 35 mg (24% of theory)

[0503] HPLC: Rt=4.23 min (HPLC method/instrument 3)

[0504] MW 562.56; m/z found: 563

[0505]¹H-NMR (200 MHz, DMSO-d₆): δ=11.71 (s, 1H); 10.40 (s, 1H); 9.16(s, 1H); 8.40 (d, 1H); 8.26 (d, 2H); 8.13 (t, 1H); 8.04-7.94 (m, 3H);7.53 (s, 1H); 7.24 (d, 1H); 7.14 (t, 1H); 6.77 (d, 1H); 1.36 (s, 3H);1.08-1.03 (m, 2H); 0.62-0.57 (m, 2H).

Example 138

[0506]1-Methyl-N-[3-({[4-(5-{6-[(methylsulphonyl)amino]-2-pyridinyl}-1,2,4-oxadiazol-3-yl)phenyl]sulphonyl}amino)phenyl]cyclopropanecarboxamide

[0507] 200 mg (0.38 mmol) of the compound from Example 134 are dissolvedin 10 ml of THF and, under argon, 0.5 ml (6.18 mmol) of pyridine and 90mg (0.75 mmol) of methanesulphonyl chloride are added. The mixture isstirred at room temperature for 16 h, the solvent is then removed underreduced pressure, the residue is taken up in 5 ml of methanol and againconcentrated under reduced pressure, and the crude product is purifiedby preparative HPLC (CromSil C18, 250×30 mm, flow rate 50 ml/min,runtime 35 min, detection at 254 nm, gradient 10% acetonitrile @ 3min->90% acetonitrile @ 31 min->90% acetonitrile @ 34 min->10%acetonitrile @ 34.01 min).

[0508] Yield: 82 mg (30% of theory)

[0509] HPLC: Rt=4.30 min (HPLC method/instrument 3)

[0510] MW 588.64; m/z found: 589

[0511]¹H-NMR (200 MHz, DMSO-d₆): δ=10.99 (br s, 1H); 10.48 (br s, 1H);9.36 (s, 1H); 8.25 (d, 1H); 8.09-7.96 (m, 4H); 7.59-7.57 (m, 1H);7.33-7.11 (m, 6H); 6.81 (d, 1H); 4.43 (d, 2H); 3.48 (5? 3H); 1.27-1.14(m, 6H).

[0512] Further 1,2,4-oxadiazole derivatives attached via position 3 andprepared according to the processes according to the invention arelisted in Table 4: Ex. m/z HPLC Rt HPLC No. Structure MW found [min]method 139

592 593 2.45 8 140

604 605 2.59 8 141

576 577 2.4 8 142

508 509 2.22 8 143

532 144

586 145

559 560 2.72 8 146

505 506 4.38 3 147

490 148

535 149

561 562 4.05 3 150

610 611 4.59 3 151

513 514 2.49 8 152

616 617 153

672 673 4.61 3 154

492 493 2.79 8

[0513] The compounds listed in the working examples and tables werecharacterized using the LC-MS and HPLC methods described below:

[0514] Method 1:

[0515] Column: Kromasil C18, L-R temperature: 30° C., flow rate 0.75 mlmin⁻¹, mobile phase: A=0.01 M HClO₄, B=CH₃CN, gradient:→0.5 min 98%A→4.5 min 10% A→6.5 min 10% A

[0516] Method 2:

[0517] Column: Kromasil C18 60×2 mm, L-R temperature: 30° C., flowrate=0.75 ml min⁻¹, mobile phase: A=0.01 M H₃PO₄, B=CH₃CN, gradient:<0.5 min 90% A→4.5 min 10% A→6.5 min 10% A

[0518] Method 3:

[0519] Column: Kromasil C18 60×2 mm, L-R temperature: 30° C., flowrate=0.75 ml min⁻¹, mobile phase: A=0.005 M HClO₄, B=CH₃CN,gradient:→0.5 min 98% A→4.5 min 10% A→6.5 min 10% A

[0520] Method 4:

[0521] Column: symmetry C18 2.1×150 mm, column oven: 50° C., flowrate=0.6 ml min⁻¹, mobile phase: A=0.6 g 30% strength HCl/1 water,B=CH₃CN, gradient: 0.0 min 90% A→4.0 min 10% A→9 min 10% A

[0522] Method 5:

[0523] LC-MS:MHZ-2Q, Instrument Micromass Quattro LCZ

[0524] Column: Symmetry C18 50 mm×2.1 mm, 3.5 μm, temperature: 40° C.,flow rate=0.5 ml min⁻¹, mobile phase A=CH₃CN+0.1% formic acid, mobilephase B=water+0.1% formic acid, gradient: 0.0 min 10% A→4 min 90% A→6min 90% A

[0525] Method 6:

[0526] LC-MS: MHZ-2P, Instrument Micromass Platform LCZ

[0527] Column: Symmetry C18 50 mm×2.1 mm, 3.5 μm, temperature: 40° C.,flow rate=0.5 ml min⁻¹, mobile phase A=CH₃CN+0.1% formic acid, mobilephase B=water+0.1% formic acid, gradient: 0.0 min 10% A→4 min 90% A→6min 90% A

[0528] Method 7:

[0529] LC-MS: MHZ-7Q, Instrument Micromass Quattro LCZ

[0530] Column: Symmetry C18 50 mm x-2.1 mm, 3.5 μm, temperature: 40° C.,flow rate=0.5 ml min⁻¹, mobile phase A=CH₃CN+0.1% formic acid, mobilephase B=water+0.1% formic acid, gradient: 0.0 min 5% A→1 min 5% A→5 min90% A→6 min 90% A

[0531] Method 8:

[0532] Column: Symmetry C18 2.1×150 mm, column oven: 50° C., flowrate=0.9 ml min⁻¹, mobile phase: A=0.3 g 30% strength HCl/1 water,B=CH₃CN, gradient: 0.0 min 90% A→3.0 min 10% A→6.0 min 10% A

[0533] Method 9:

[0534] HP1100, column: LiChroCart 75-5 LiChrospher 100 RP-18 5 μm,column oven: 40° C., flow rate=2.5 ml min⁻¹, mobile phase: A=waterhaving 0.05% TFA, B=CH₃CN having 0.05% TFA, gradient: 0.0 min 90% A→0.05min 90% A→5.0 min 5% A→7.0 min 5% A→7.05 min 90% A→8.0 min 90% A

1. Compounds of the general formula (I)

in which R² and R³ are identical or different and represent hydrogen,hydroxyl, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or represent a group of the formula

 in which R⁵, R⁶ and R⁷ are identical or different and each representshydrogen or (C₁-C₆)-alkyl which for its part may be substituted by oneor two substituents selected from the group consisting of hydroxyl,halogen, cyano, trifluoromethyl and trifluoromethoxy, A represents five-or six-membered heteroaryl, which is attached to the adjacent phenylring via a C atom and has one to three heteroatoms selected from thegroup consisting of N, O and S, R¹ represents (C₆-C₁₀)-aryl, 5- to10-membered heteroaryl or 5- to 10-membered heterocyclyl having in eachcase one to three heteroatoms selected from the group consisting of N, Oand S, where R¹ may be substituted by up to three substituents selectedfrom the group consisting of hydroxyl, amino, mono-(C₁-C₆)-alkylamino,di-(C₁-C₆)-alkylamino, halogen, nitro, cyano, oxo, (C₁-C₆)-alkyl, whichfor its part may be substituted by amino or hydroxyl, (C₁-C₆)-alkoxy,phenyl, 5- or 6-membered heterocyclyl having up to two heteroatomsselected from the group consisting of N, O and S, 5- or 6-memberedheteroaryl having one or more heteroatoms selected from the groupconsisting of N, O and S, —C(O)—O—R⁸, —C(O)—NR⁹R¹⁰, —NH—C(O)—R¹¹,—NH—C(O)—C(O)—R¹² and —NH—SO₂—R¹³,  where R⁸, R⁹ and R¹⁰ are identicalor different and each represents hydrogen or (C₁-C₆)-alkyl, or R⁹ andR¹⁰ together with the nitrogen atom to which they are attached form a 5-or 6-membered heterocycle which may contain a further nitrogen or oxygenheteroatom and which may be mono- or disubstituted by identical ordifferent substituents from the group consisting of (C₁-C₄)-alkyl, whichfor its part is optionally substituted by hydroxyl or amino, amino,hydroxyl, (C₁-C₄)-alkoxy, oxo, carboxyl and (C₁-C₄)-alkoxycarbonyl, R¹¹and R¹² are identical or different and each represents trifluoromethyl,(C₁-C₆)-alkoxy, hydroxyl or represents (C₁-C₆)-alkyl; which isoptionally mono- or disubstituted by identical or different constituentsfrom the group consisting of amino, (C₁-C₆)-alkoxycarbonylamino,mono-(C₁-C₆)-acyl-amino, hydroxyl, amidino, guanidino,(C₁-C₆)-alkoxycarbonyl, carboxyl and phenyl, and R¹³ represents(C₁-C₆)-alkyl or (C₆-C₁₀)-aryl which may in each case be substituted byhalogen, amino, hydroxyl, (C₁-C₄)-alkoxy or (C₁-C₄)-alkyl, R⁴ represents(C₁-C₆)-alkyl which may be substituted up to three times by identical ordifferent substituents from the group consisting of amino, hydroxyl,halogen, (C₁-C₆)-alkoxy, (C₁-C₅)-alkanoyloxy and phenyl, which for itspart is optionally mono- or disubstituted by identical or differentsubstituents from the group consisting of halogen, nitro, cyano, aminoand hydroxyl, represents (C₃-C₇)-cycloalkyl which may be substituted upto three times by identical or different substituents from the groupconsisting of amino, hydroxyl, halogen, (C₁-C₆)-alkoxy and(C₁-C₆)-alkyl, which for its part is optionally substituted up to threetimes by identical or different substituents from the group consistingof amino, hydroxyl, halogen and (C₁-C₆)-alkoxy, or represents(C₆-C₁₀)-aryl which is optionally mono- or disubstituted by identical ordifferent substituents from the group consisting of halogen, nitro,cyano, amino and hydroxyl, and in which X represents oxygen or sulphur,and in which nitrogen-containing heterocycles may also be present asN-oxides, and their tautomers, stereoisomers, stereoisomer mixtures andtheir pharmacological acceptable salts.
 2. Compounds of the generalformula (I) according to claim 1, in which R² and R³ are identical ordifferent and represent hydrogen, hydroxyl, halogen, nitro, cyano,trifluoromethyl, trifluoromethoxy, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy orrepresent a group of the formula

 in which R⁵, R⁶ and R⁷ are identical or different and each representshydrogen of (C₁-C₆)-alkyl, which for its part may be substituted by oneor two substituents selected from the group consisting of hydroxyl,halogen, cyano, trifluoromethyl and trifluoromethoxy, A represents five-or six-membered heteroaryl, which is attached to the adjacent phenylring via a C atom and has one to three heteroatoms selected from thegroup consisting of N, O and S, R¹ represents (C₆-C₁₀)-aryl, 5- to10-membered heteroaryl or 5- to 10-membered heterocyclyl having in eachcase one to three heteroatoms selected from the group consisting of N, Oand S, where R¹ may be substituted by up to three substituents selectedfrom the group consisting of hydroxyl, amino, mono-(C₁-C₆)-alkylamino,di-(C₁-C₆)-alkylamino, halogen, nitro, cyano, oxo, (C₁-C₆)-alkyl, whichfor its part may be substituted by amino or hydroxyl, (C₁-C₆)-alkoxy,phenyl, 5- or 6-membered heteroaryl having one or more heteroatomsselected from the group consisting of N, O and S, —C(O)—O—R⁸,—C(O)—NR⁹R¹⁰ and —NH—C(O)—R”,  where R⁸, R⁹ and R¹⁰ are identical ordifferent and each represents hydrogen or (C₁-C₆)-alkyl, and R¹¹represents (C₁-C₆)-alkyl which is optionally mono- or disubstituted byidentical or different substituents from the group consisting of amino,hydroxyl, guanidino, carboxyl and phenyl, R⁴ represents (C₁-C₆)-alkylwhich may be substituted up to three times by identical or differentsubstituents from the group consisting of amino, hydroxyl, halogen,(C₁-C₆)-alkoxy and phenyl, which for its part is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of halogen, nitro, cyano, amino and hydroxyl, represents(C₃-C₇)-cycloalkyl which may be substituted up to three times byidentical or different substituents from the group consisting of amino,hydroxyl, halogen, (C₁-C₆)-alkoxy and (C₁-C₆)-alkyl, which for its partis optionally substituted up to three times by identical or differentsubstituents from the group consisting of amino, hydroxyl, halogen and(C₁-C₆)-alkoxy, or represents (C₆-C₁₀)-aryl which is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of halogen, nitro, cyano, amino and hydroxyl, and in which Xrepresents oxygen or sulphur, and in which nitrogen-containingheterocycles may also be present as N-oxides, and their tautomers,stereoisomers, stereoisomer mixtures and their pharmacologicallyacceptable salts.
 3. Compounds of the general formula (I) according toclaim 1, in which R² and R³ are identical or different and representhydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl,trifluoromethoxy, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy or represent a group ofthe formula

 in which R⁵, R⁶ and R⁷ are identical or different and each representshydrogen or (C₁-C₆)-alkyl, which for its part may be substituted by oneor two substituents selected from the group consisting of hydroxyl,halogen, cyano, trifluoromethyl and trifluoromethoxy, A represents five-or six-membered heteroaryl, which is attached to the adjacent phenylring, via a C atom and has one to three heteroatoms selected from thegroup consisting of N, O and S, R¹ represents (C₆-C₁₀)-aryl, 5- to10-membered heteroaryl or 5- to 10-membered heterocyclyl having in eachcase one to three heteroatoms selected from the group consisting of N, Oand S, where R¹ may be substituted by up to three substituents selectedfrom the group consisting of hydroxyl, amino, mono-(C₁-C₆)-alkylamino,di-(C₁-C₆)-alkylamino, halogen, nitro, cyano, oxo, (C₁-C₆)-alkyl, whichfor its part may be substituted by amino or hydroxyl, (C₁-C₆)-alkoxy,phenyl, 5- or 6-membered heteroaryl having one or more heteroatomsselected from the group consisting of N, O and S, —C(O)—O—R⁸,—C(O)—NR⁹R¹⁰ and —NH—C(O)—R¹¹,  where R⁸, R⁹ and R¹⁰ are identical ordifferent and each represents hydrogen or (C₁-C₆)-alkyl, and R¹¹represents (C₁-C₆)-alkyl, which is optionally mono- or disubstituted byidentical or different substituents from the group consisting of amino,hydroxyl, guanidino, carboxyl and phenyl, R⁴ represents (C₁-C₆)-alkylwhich may be substituted up to three times by identical or differentsubstituents from the group consisting of amino, hydroxyl, halogen,(C₁-C₆)-alkoxy and phenyl, which for its part is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of halogen, nitro, cyano, amino and hydroxyl, represents(C₃-C₇)-cycloalkyl which may be substituted up to three times byidentical or different substituents from the group consisting of amino,hydroxyl, halogen, (C₁-C₆)-alkoxy and (C₁-C₆)-alkyl, which for its partis optionally substituted up to three times by identical or differentsubstituents from the group consisting of amino, hydroxyl, halogen and(C₁-C₆)-alkoxy, or represents (C₆-C₁₀)-aryl which is optionally mono- ordisubstituted by identical or different substituents from the groupconsisting of halogen, nitro, cyano, amino and hydroxyl, and in which Xrepresents oxygen, and in which nitrogen-containing heterocycles mayalso be present as N-oxides, and their tautomers, stereoisomers,stereoisomer mixtures and their pharmacologically acceptable salts. 4.Compounds of the general formula (I) according to claim 1, in which R²and R³ are identical or different and represent hydrogen or halogen, Arepresents the radical (A-I)

which is attached to the adjacent phenyl ring via one of the carbonatoms in position 3 or 5, and in which Y represents oxygen or sulphur,or A represents the radical (A-II)

which is attached to the adjacent phenyl ring via one of the carbonatoms in position 2 or 5, and in which Y represents oxygen or sulphur,R¹ represents 5- to 10-membered heteroaryl or 5- or 10-memberedheterocyclyl having in each case up to three heteroatoms selected fromthe group consisting of N, O and S, or represents phenyl, where R¹ maybe substituted by one to three substituents selected from the groupconsisting of (C₁-C₄)-alkyl, which for its part is optionallysubstituted by hydroxyl or amino, hydroxyl, oxo, halogen, amino,mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino and —NH—C(O)—R¹¹, whereR¹¹ represents (C₁-C₆)-alkyl which is optionally mono- or disubstitutedby identical or different substituents from the group consisting ofamino, hydroxyl, guanidino and carboxyl, R⁴ represents (C₁-C₄)-alkylwhich may be substituted up to three times by identical or differentsubstituents from the group consisting of amino, hydroxyl, fluorine,chlorine and (C₁-C₄)alkoxy, represents (C₃-C₅)-cycloalkyl, which may besubstituted up to three times by identical or different substituentsfrom the group consisting of amino, hydroxyl, fluorine, chlorine,(C₁-C₄)-alkoxy and (C₁-C₄)-alkyl, which for its part is optionallysubstituted up to three times by identical or different substituentsfrom the group consisting of amino, hydroxyl, fluorine, chlorine and(C₁-C₄)-alkoxy, and in which X represents oxygen or sulphur, and inwhich nitrogen-containing heterocycles may also be present as N-oxides,and their tautomers, stereoisomers, stereoisomer mixtures and theirpharmacologically acceptable salts.
 5. Compounds of the general formula(I) according to claim 1, in which R² and R³ are identical or differentand represent hydrogen or halogen, A represents the radical (A-I)

which is attached to the adjacent phenyl ring via one of the carbonatoms in position 3 or 5, and in which Y represents oxygen or sulphur,or A represents the radical (A-II)

which is attached to the adjacent phenyl ring via one of the carbonatoms in position 2 or 5, and in which Y represents oxygen or sulphur,R¹ represents 5- to 10-membered heteroaryl or 5- or 10-memberedheterocyclyl having in each case up to three heteroatoms selected fromthe group consisting of N, O and S, or represents phenyl, where R¹ maybe substituted by one to three substituents selected from the groupconsisting of (C₁-C₄)-alkyl, which for its-part is optionallysubstituted by hydroxyl or amino, hydroxyl, oxo, halogen, amino,mono-(C₁-C₄)-alkylamino, di-(C₁-C₄)-alkylamino and —NH—C(O)—R¹¹, whereR¹¹ represents (C₁-C₆)-alkyl which is optionally mono- or disubstitutedby identical or different substituents from the group consisting ofamino, hydroxyl, guanidino and carboxyl, R⁴ represents (C₁-C₄)-alkylwhich may be substituted up to three times by identical or differentsubstituents from the group consisting of amino, hydroxyl, fluorine,chlorine and (C₁-C₄)-alkoxy, or represents (C₃-C₅)-cycloalkyl which maybe substituted up to three times by identical or different substituentsfrom the group consisting of amino, hydroxyl, fluorine, chlorine,(C₁-C₄)-alkoxy and (C₁-C₄)-alkyl, which for its part is optionallysubstituted up to three times by identical or different substituentsfrom the group consisting of amino, hydroxyl, fluorine, chlorine and(C₁-C₄)-alkoxy, and in which X represents oxygen, and their tautomers,stereoisomers, stereoisomer mixtures and their pharmacologicallyacceptable salts.
 6. Compounds of the general formula (1) according toclaim 1, in which R² and R³ represent hydrogen, A represents one of theradicals

R¹ represents a radical selected from the group consisting of phenyl,pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl,oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and indolyl, where R¹ may besubstituted by one or two substituents selected from the groupconsisting of methyl, aminomethyl, hydroxyl, bromine, chlorine,fluorine, amino, dimethylamino and —NH—C(O)—R¹¹, where R¹¹ represents(C₁-C₆)-alkyl which is optionally mono- or disubstituted by identical ordifferent substituents from the group consisting of amino, hydroxyl,guanidino and carboxyl, R⁴ represents tert-butyl which is optionallysubstituted up to three times by identical or different substituentsfrom the group consisting of hydroxyl, fluorine and chlorine, orrepresents cyclopropyl or cyclobutyl which are substituted by methyl,which for its part is optionally substituted by hydroxyl, fluorine orchlorine, and in which X represents oxygen, and in whichnitrogen-containing heterocycles may also be present as N-oxides, andtheir tautomers, stereoisomers, stereoisomer mixtures and theirpharmacologically acceptable salts.
 7. Compounds of the general formula(I) according to claim 1, in which R² and R³ represent hydrogen, Arepresents one of the radicals

R¹ represents a radical selected from the group consisting of phenyl,pyridyl, pyrazinyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl,oxazolyl, pyrazolyl, imidazolyl, pyrrolyl and indolyl, where R¹ may besubstituted by one or two substituents selected from the groupconsisting of methyl, aminomnethyl, hydroxyl, bromine, chlorine,fluorine, amino, dimethylamino and —NH—C(O)—R¹¹, where R¹¹ represents(C₁-C₆)-alkyl which is optionally mono- or disubstituted by identical ordifferent substituents from the group consisting of amino, hydroxyl,guanidino and carboxyl, R⁴ represents tert-butyl which is optionallysubstituted up to three times by identical or different substituentsfrom the group consisting of hydroxyl, fluorine and chlorine, orrepresents cyclopropyl or cyclobutyl which are substituted by methyl,which for its part is optionally substituted by hydroxyl, fluorine orchlorine, and in which X represents oxygen.
 8. Compounds according toclaim 1 of the general formula (Ia)

in which R¹, R⁴, A and X are as defined above, and R² and R³ areidentical or different and represent hydrogen, hydroxyl, halogen, nitro,cyano, trifluoromethyl, trifluoromethoxy, (C₁-C₆)-alkyl or(C₁-C₆)-alkoxy.
 9. Compounds of the general formula (I) according toclaim 1, in which R⁴ represents one of the radicals


10. Compounds of the general formula (1) according to claim 1, in whichA represents a 1,2,4-oxadiazole attached via the 3-position. 11.Compounds according to claim 1, selected from the group of the followingcompounds:


12. Process for preparing compounds of the general formula (I) accordingto claim 1, in which A represents the radical (A-I)

which is attached to the adjacent phenyl ring via one of the carbonatoms in position 3 or 5, and in which Y represents oxygen, by reactingamidoximes of the general formula [D-1]

in which X, R², R³ and R⁴ are as defined above, with a carboxylic acid[E-1] R¹—COOH  [E-1] in which R¹ is as defined above, or condensingsulphonamides of the general formula [F-3]

in which X, R², R³ and R⁴ are as defined above, with an amidoxime of thegeneral formula [G-1]

in which R¹ is as defined above, giving compounds of the general formula[G-2],

in which R¹, R², R³, R⁴ and X are as defined above, and subsequentlycyclizing the compounds [G-2] with elimination of water, giving thecompounds of the general formula (1).
 13. Process for preparingcompounds of the general formula (I) according to claim 1 in which Arepresents the radical (A-II)

which is attached to the adjacent phenyl ring via one of the carbonatoms in position 2 or 5, and in which Y represents oxygen, by cyclizinghydrazides of the general formula [H-2]

in which X, R¹, R², R³ and R⁴ are as defined above, and FH representshydrogen, an amino protective group or a polymeric support, withelimination of water, to give compounds of the general formula (I). 14.Process for preparing compounds of the general formula (I) according toclaim 1, in which X represents oxygen, A represents the radical (A-II)

which is attached to the adjacent phenyl ring via one of the carbonatoms of position 2 or 5, and in which Y represents sulphur, bycyclizing hydrazides of the general formula [H-3]

in which R¹, R², R³ are as defined above, FH represents hydrogen, anamino protective group or a polymeric support, and R⁴′ represents(C₁-C₆)-alkoxy, (C₁-C₆)-alkenoxy or aralkoxy, in the presence of a thiodonor, preferably Lawesson's reagent, to give compounds of the generalformula (I) in which Y represents sulphur, then removing group—C(O)—R^(4′) and finally reacting with compounds of the general formula

in which R⁴ and Q are as defined above.
 15. Use of compounds of thegeneral formula (I) according to any of claims 1 to 11 for theprophylaxis or treatment of diseases.
 16. Use of compounds of thegeneral formula (I) according to any of claims 1 to 11 for preparingmedicaments.
 17. Use of compounds of the general formula (I) accordingto claim 16, where the medicaments are for controlling viral disorders.18. Use of compounds of the general formula (I) according to claim 16 or17, where the medicaments are for controlling cytomegalovirusinfections.
 19. Medicaments, comprising compounds of the general formula(I) according to claim
 1. 20. Compounds of the general formula (Ia)according to claim 1

in which R¹, R², R³, R⁴, A and X are as defined above.